Method of healing skin wounds in mammals and a composition therefor

ABSTRACT

This invention pertains to therapeutic antibacterial/antifungal-wound healing compositions comprising a therapeutically effective amount of antibacterial agents and/or antifungal agents and/or wound healing composition alone. In one embodiment, the wound healing composition comprises (a) zinc oxide; (b) calcium channel blocker, and (c) fat-soluble vitamins admixed with antibacterial and antifungal agents. The therapeutic antibacterial/antifungal-wound healing compositions may be utilized in a wide variety of pharmaceutical products and administered orally or topically.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of my application Ser. No.10/125,165 filed on Apr. 18, 2002 entitled “Wound Healing Compound,”which is now U.S. Pat. No. 6,660,306, which is a continuation-in-part ofmy application Ser. No. 09/689,087 filed on Oct. 12, 2000 entitled“Wound Healing Compound,” now abandoned, the full disclosures of whichare incorporated by reference herein.

This invention pertains to therapeutic antibacterial/antifungal-woundhealing compositions useful for reducing the size, duration, andseverity of wounds both infected and non-infected. More particularly,the antibacterial/antifungal-wound healing compositions comprise anantibacterial agent and/or, an antifungal agent, and a therapeutic woundhealing composition and/or its metabolites. A preferred embodiment ofthe therapeutic wound healing composition of this invention comprises(a) zinc oxide and, (b) an admixture of two or more of the four fatsoluble vitamins.

BACKGROUND OF INVENTION

-   Wound Healing

Wounds are internal or external bodily injuries or lesions caused byphysical means, such as mechanical, chemical, viral, bacterial, fungaland other pathogenic organisms, or thermal means, which disrupt thenormal continuity of tissue structure. Such bodily injuries includecontusions, wounds in which the skin is unbroken, incisions, wounds inwhich the skin is broken cutting instrument, and lacerations, wounds inwhich the skin is broken by a dull or, blunt instrument. Wounds may becaused by accident, surgery, pathological organisms, or by surgicalprocedures. Patients who suffer wounds could benefit from anantibacterial/antifungal-wound healing composition.

Wound healing consists of a series of processes whereby injured tissueis repaired, specialized tissue is regenerated, and new tissue isreorganized. Wound healing consists of three major phases: a) aninflammation stage (0-3 days), b) proliferation stage (3-12 days), andc) a remodeling phase (3 days to 6 months).

During the inflammation phase, platelet aggregation and clotting from amatrix which traps the plasma proteins and blood cells to induce theinflux of various types of cells. During the cellular proliferationphase, new connective or granulation tissue and blood vessels areformed. During the remodeling phase, granulation tissue is replaced by anetwork of collagen and elastin fibers leading to the formation of scartissue.

When cells are injured or killed as the result of a wound, a woundhealing step is desirable to resuscitate the injured cells and producenew cells to replace the dead cells. The healing process requires thereversal of cytotoxicity, the suppression of inflammation, and thestimulation of cellular viability and proliferation. Wounds require lowlevels of oxygen in the initial stages of healing to suppress theoxidative damage and higher levels of oxygen in the later stages ofhealing to promote collagen formation by fibroblasts.

Mammalian cells are continuously exposed to activate oxygen species suchas superoxide (O.sub.2—), hydrogen peroxide (H.sub.2.0.sub.2.), hydroxylradical (OH), and singlet oxygen (.sup.1O.sub.2.). In vivo, thesereactive oxygen intermediates are generated by cells in response toaerobic metabolism, catabolism of drugs and other xenobitics,ultraviolet and x-ray radiation, and the respiratory burst of phagocyticcells (such as white blood cells) to kill invading bacteria such asthose introduced through wounds. Hydrogen peroxide, for example, isproduced during respiration of most living organisms especially bystressed and injured cells.

These active oxygen species can injure cells. An important example ofsuch damage is lipid peroxidation which involves the oxidativedegradation of unsaturated lipids. Lipid peroxidation is highlydetrimental to membrane structure and function and can cause numerouscytopathological effects. Cells defend against lipid peroxidation byproducing radical scavengers such as superoxide dismutase, catalase, andperoxidase. Injured cells have a decreased ability to produce radicalscavengers. Excess hydrogen peroxide can react with DNA to causebackbone breakage, produce mutations, and alter and liberate bases.Hydrogen peroxide can also react with pyrimidines to open the 5,6-doublebond, which reaction inhibits the ability of pyrimidines to hydrogenbond to complementary bases, Hallaender, et al. (1971). Such oxidativebiochemical injury can result in the loss of cellular membraneintegrity, reduced enzyme activity, changes in transport kinetics,changes in membrane lipid content and leakage of potassium ions, aminoacids and other cellular material.

Antioxidants have been shown to inhibit damage associated with activeoxygen species. For example, pyruvate and other Alpha-keotacids havebeen reported to react rapidly and stoichiometrically with hydrogenperoxide to protect cells from cyt9olytic effects, O'Donnell=Tormey etal., J. Exp. Med., 165, pp. 500-514 (1987).

SUMMARY OF THE INVENTION

This invention pertains to therapeutic antibacterial/antifungal-woundhealing compositions for reducing the size, duration and severity ofwounds both infected and non-infected. The compositions of the inventioncomprise a therapeutically effective amount of one or more antibacterialagents and/or, one or more antifungal agents, and a wound healingcomposition. A preferred embodiment of the wound healing composition ofthis invention comprises (a) zinc oxide and, (b) an admixture of two ormore of the four fat soluble vitamins. The therapeuticantibacterial/antifungal-wound healing compositions of this inventionmay be utilized in a wide variety of pharmaceutical products.

This invention also comprises augmented therapeuticantibacterial/antifungal-wound healing compositions comprisingantibacterial agents, antifungal agents, and a therapeutic sound healingcomposition in combination with one or more medicament. This inventionalso relates to methods for preparing and using the augmentedtherapeutic antibacterial/antifungal-wound healing compositions and thepharmaceutical products in which the augmented compositions may be used.

These and other objects of the present invention are achieved through aprovision of a method of treating skin wounds in mammals by topicalapplication of a therapeutic composition, which comprises zinc oxide,Vitamins A, D, E, and K, bacitracin zinc, clotrimazole and a calciumchannel blocker. In a preferred embodiment, the composition comprisesbetween about 0.01% and about 75% by total weight of zinc oxide, betweenabout 0.01% and 99.99% by total weight of a combined amount offat-soluble vitamins A, D, E, and K, between about 0.0001% and about 50%by total weight of a calcium channel blocker, an effective amount ofantimicrobial agent and an effective amount of an antifungal agent.

Generally, calcium channel blockers block L-type calcium channels andcause dilation of peripheral blood vessels, reducing peripheralresistance and facilitating absorption of the healing compound into thesystem. The calcium channel blocker is preferably dihydropyridinecalcium channel blocker, such as nifedipine. More specifically,nifedipine is 3,5-pyridinedicarboxylic acid,1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-dimethyl ester, which has thechemical formula of C₁₇H₁₈N₂O₆.

In the preferred embodiment, Vitamin A is selected from the groupconsisting of retinol, 3,4-didehydroretinol, carotene, alpha-carotene,beta-carotene, delta-carotene, and gamma carotene; Vitamin D is selectedfrom the group consisting of cholecalciferol and ergocalciferol; VitaminE is selected from the group consisting of Vitamin E acetate, Vitamin Esuccinate, pharmaceutically acceptable Vitamin E salts and Vitamin Ephosphate.

In the preferred embodiment, antibacterial agents are selected from thegroup consisting of bismuth-containing compounds, sulfonamides,nitrofurans, metronidazole, nimorazole, tinidazole, benzoic acid,aminoglycosides, macrolides, penicillins, polypeptides, tetracyclines,cephalosporins, chloramphenicol, clindamycin and mixtures thereof. Inmore preferred embodiments, the antibacterial agents are selected fromthe group consisting of bismuth aluminate, bismuth subcitrate, bismuthsubgalate, bismuth subsalicylate, sulfonamides, nitrofurazone,nitrofurantoin, furazolidone, metronidazole, tinidazole, nimorazole,benzoic acid, hentamycin, neomycin, kynamycin, streptomycin,erythromycin, clindamycin, rifampin, rifamycin, penicillin G, penicillinV, ampicillin, amoxicillin, bacitracin, polymyxin, tetracycline,chlortetracycline, oxytetracycline, doxycycline, cephalexin,cephalothin, clindamycin, chloramphenical and mixtures thereof. In themost preferred embodiment, the antibacterial agent is bacitracin zinc.

The antifungal agents are selected from the group consisting ofastemizole, clotrimazole, omeprazole, econazole, oxiconazole,sulconazole, fluconazole, ketoconazole, itraconazole, torbinafine, andmixtures thereof. In the most preferred composition, the antifungalagent is clotrimazole.

DETAILED DESCRIPTION OF THE INVENTION

First used in the 1980s, calcium channel blockers (also called calciumantagonists) are non-habit-forming medications that prevent the flow ofcalcium ions into the muscle cells of the heart. The therapeutic effectof the calcium channel blockers is dilation of coronary and peripheralblood vessels, which results in a reduced peripheral resistance. As aresult, the calcium channel blockers facilitate absorption of thevitamins, antibacterial and antifugal agents into the system.

In the preferred embodiment, the therapeutic compound of the presentinvention comprises between 0.0001 to 50 wt % of a calcium channelblocker, such as dihydropyridine calcium channel blocker, for instancenifedipine. In the most preferred embodiment, the compound of thepresent invention contains 2% by total weight of nifedipine. It ispreferred that nifedipine is added and mixed with the remainder ofingredients in the absence of light.

This invention pertains to antibacterial/antifungal-wound healingcompositions which comprise one or more antibacterial agents, one ormore antifungal agents, and a wound healing composition or itsmetabolites. In one embodiment the wound healing composition comprises(a) zinc oxide and (b) an admixture of two or more of the four fatsoluble vitamins.

Applicant has discovered therapeutic wound healing compositions forpreventing and reducing injuries to mammalian cells and increasing theresuscitation rate of injured mammalian cells. Wounds treated with thetherapeutic wound healing composition showed significantly improvedwound closing and healing one untreated over untreated wounds and woundstreated by other means including other conventional wound healingcompositions. The wound healing compositions may be used alone or withother medicaments.

The therapeutic wound healing compositions of this invention areEmbodiment One. There are several aspects of Embodiment One oftherapeutic wound healing compositions in this invention. In a firstaspect, (I.A), the therapeutic wound healing composition comprises (a)zinc oxide and (b) an admixture o two or more of the four fat-solublevitamins.

The therapeutic wound healing compositions of this invention are furthercombined with a therapeutically effective amount of antibacterial agent(X) and/or a therapeutically effective amount of antifungal (Y) to formthe antibacterial/antifungal-wound healing compositions (I.A-X+Y). Theantibacterial/antifungal-wound healing compositions may be alone or incombination with other medicaments. This invention also pertains tomethods for preparing and using the antibacterial/antifungal-woundhealing compositions and the pharmaceuticals products in which thetherapeutic compositions may be used.

The therapeutic antibacterial/antifungal-wound healing compositions ofthis invention may be further combined with one or more additionalmedicaments for treating wounds to form augmentedantibacterial/antifungal-wound healing compositions. This invention alsorelates to methods for preparing and using the augmented therapeuticantibacterial/antifungal-wound healing compositions and thepharmaceutical products in which the augmented compositions may be used.

The term “injured cell” as used herein means a cell that has anyactivity disrupted for any reason. For example, an injured cell may be acell that has injured membranes or damaged DNA, RNA, and ribisomes, forexample, a cell which as (a) injured membranes so that transport throughthe membranes is diminished resulting in an increase in toxins andnormal cellular wastes inside the cell and a decrease in nutrients andother components necessary for cellular repair inside the cell (b) anincrease in concentration of oxygen radicals inside the cell because ofthe decreased ability of the cell to produce antioxidants and enzymes,or (c) damaged DNA, RNA, and ribisomes which must be repaired orreplaced before normal cellular functions can be resumed. The term“resuscitation” of injured mammalian cells as used herein means thereversal of cytotoxicity, the stabilization of the cellular membrane, anincrease in the proliferation rate of the cell, and/or the normalizationof the cellular functions such as the secretion of growth factors,hormones and the like. The term “cytotoxity” as used herein means acondition caused by a cytotoxic agent that injures the cell. Injuredcells do not proliferate because injured cells expend all energy oncellular repair. Aiding cellular repair prompts cellular proliferation.

The term “precursor”, as used herein, refers to compounds which undergobiotransformation prior to exhibiting their pharmacological effects. Thechemical modification of drugs to overcome pharmaceutical problems hasalso been termed “drug latentiation.” Drug latentiation is the chemicalmodification of a biologically active to form a new compound which uponin vivo/vitro enzymatic attack will liberate the parent compound. Thechemical alterations of the parent compound are such that the change inphysiochemical properties will affect the absorption, distribution, andenzymatic metabolism. The definition of drug latentiation has also beenextended to include non-enzymatic regeneration of the parent compound.Regeneration takes place as a consequence of hydrolytic, disassociative,and other reactions not necessarily enzyme medicated. The termsprecursor, prodrugs, latentiated drugs, and bioreversible derivativesare used interchangeably. By inference, latentiation implies a time lagelement or time component involved in regenerating the bioactive parentmolecule in vivi. The termis prodrug and precursor are general in thatthey include latentiation drug derivatitives as well as those substanceswhich are converted after administration to the actual substance whichcombines with receptors. The term prodrug is a generic term for agentswhich undergo biotransformation prior to exhibiting theirpharmacological actions. In the case where the administered drug is notthe active agent, but is rater biotransformed to the active agent. Theterm prodrug also includes compounds which may not necessarily undergobiotransformation to the administered drug but may undergobiotransformation to the active agent which exhibits the desiredpharmacological effect.

The term “metabolite”, as used herein, refers to any substance producedby the metabolism or by a metabolic process. Metabolism, as used herein,refers to the various chemical/biochemical reactions involved in thetransformation of molecules or chemical compounds occurring in the cellstherein.

I. Wound Healing Compositions.

A. Embodiment One (I.A-F)

The cells which may be treated with the therapeutic wound healingcompositions in the present invention are mammalian cells. Althoughapplicant will describe the present therapeutic wound healingcompositions as useful for treating mammalian epidermal keratinocytesand mammalian monocytes, and cells of the subcutaneous tissues, andmuscle tissues, and bone and applicant contemplates that the therapeuticwound healing compositions may also be used to protect or resuscitateall mammalian cells. Keratinocytes are representative of normalmammalian cells and are the fastest proliferating cells in the body. Thecorrelation between the reaction of keratinocytes to injury and therapyand that of mammalian cell in general is very high. Monocytes arerepresentative of specialized mammalian cells such as white blood cellsin the immune system and the organ cells in the liver, kidney, heart andbrain. The mammalian cells may be treated in vivo or in vitro.

Epidermal keratinocytes are the specialized cell of the epidermis whichsynthesize keratin, a scleroprotein which is a principal constituent ofepidermis, hair, nails, horny tissue, and the organic matrix of theenamel of teeth. Mammalian epidermal keratinocytes constitute about 95%of the epidermal cells and together with the melanocytes form the binarysystem of the epidermis. In its various successive stages, epidermalkeratinocytes are also known as basal cells, prickle cells, and granularcells. Monocytes are mononuclear leukocytes which undergo respiratorybursting and are involved in reactive oxygen medicated damage within theepidermis. Leukocytes are white blood cells or corpuscles which may beclassified into two main groups: granular leukocytes (granulocytes)which are leukocytes with abundant granules in the cytoplasm andnongranular leukocytes (nongraulocytes) which are lueukocytes withoutspecific granules in the cytoplasm and which include the lymphocytes andmonocytes. Phagocyte cells are cells which ingest microorganisms orother cells and foreign particles. Monocytes are also know as largemononuclear leukocytes, and hyaline or transitional leukocytes.

Epidermal keratinocytic cells and monocytic cells have multiple oxygengenerating mechanisms and the degree to which type of mechanismfunctions differs in each type of cell. In monocytes, for example, therespiratory bursting process is more pronounced than in dermalkeratinocytes. Hence, the components in the therapeutic wound healingcompositon may vary depending upon the types of cells involved in thecondition being treated.

As set out above, in the first aspect of Embodiment One (I.A), thetherapeutic wound healing composition for treating mammalian cellscomprises (a) zinc oxide and, (b) all forms and precursors of Vitamin Aand, (c) all forms and presurors of Vitamin D. In a second aspect ofEmbodiment One (I.B), the therapeutic wound healing composition fortreating mammalian cells comprises (a) zinc oxide and, (b) all forms andprecursors of Vitamin A and (c) all forms and precursors of Vitamin Dand (d) all forms and precursors of Vitamin E. In a third aspect ofEmbodiment (I.C), the therapeutic wound healing composition for treatingmammalian cells comprises (a) zinc oxide and, (b) all forms andprecursors of A and, (c) all forms and precursors of Vitamin D and, (d)all forms and precursors of Vitamin K.

Zinc oxide has been shown to be an essential catalyst in manybiochemical reactions. Zinc has been reported to display antibacterialeffects. Zinc oxide has also been shown to maintain a constant level ofzinc when applied to wounds as compared to salts of zinc.Re-epitheliaization is enhanced when zinc oxide is present. Inflammatoryreaction has been shown to be reduced with adequate zinc concentration.Zinc oxide promotes cleansing of wounds and decreases deterioration ofexisting wounds. It has also been reported that the application of zincoxide to wounds not only corrects the local zinc deficiency but alsoacts pharmacologically Patients with diabetes mellitus have been notedas having zinc deficiencies related to impaired wound healing. Zincoxide has also been shown to be effective in healing donor sites fromskin grafting.

Application of zinc oxide has been shown to accelerate the healing ofboth chronic and acute wounds and increases endogenous gene expressionof insulin-like growth factor-1 in granulation tissue.

Vitamin A plays an important role in the orderly differentiation ofepithelium. The mechanism is not precisely understood, however in cellculture systems, Vitamin A regulates the gene expression of a number ofcell receptors and secreted proteins, including receptors for growthfactors. It is also reported that Vitamin A plays a role in theevolution of granulation tissue. Vitamin A have been shown to visiblyaccelerate wound healing after thermal injury including tissues whichwere previously believed to be irreparable. It has also been shown thatto Vitamin A accelerates epidermal cell and subcutaneous tissue as wellas fibroblast proliferation after UV injury and these were shown to bedose related. Vitamin A has also been shown to be effective in thetreatment of cancers, acne, and psoriasis and is essential for visionand occular tissue formation.

Vitamin D has been shown to be a potent agonist of the Vitamin Dreceptor which stimulates glycosaminoglycan synthesis and transforminggrowth factor-beta 1 (TGF-beta 1) thereby accelerating wound healing.Vitamin D has been shown to be an effective treatment for chronic legwounds. It is reported that Vitamin D promotes dermal wound strength andre-epithelialization as well as enhancing granulation tissue formation.It has also been shown to be effective in preventing osteomyelitis.Vitamin D increases the absorption of calcium in mammalian cells. It canalso prevent secondary hypothyroidism in elderly patients with renalinsufficiency and has been shown to possibly prevent breast cancer. Ithas also been evidenced that Vitamin D may slow the progress of subclinical to clinically significant prostate cancer. Deficiency ofVitamin D has been known to cause rickets and hypocalcemic seizures.Vitamin D is also a membrane antioxident. Vitamin D has also been shownto increase the absorption of magnesium and bone mineral contents inmammals and may improve prevention and treatment of renalosteodystrophy. There is a link reported between Vitamin D levels andthe severity of rheumatoid arthritis with those patients with moreseverity of the disease are shown to be the most deficient in thisimportant vitamin. Vitamin D and calcium deficiencies have been relatedto migraine headaches in post menopausal females. Vitamin D has alsobeen shown to be a treatment for psoriasis.

Vitamin E has been shown to be effective in promoting enhanced fibrosisof tissues. It has also been shown to be an antioxidant. Muscleweakness, ataxia, sensory impairment, vision abnormalities, anddysarthria have been reported as due to Vitamin E deficiency. Vitamin Ehas also been shown to accelerate wound healing including gingivalwounds. It has also been shown to prevent endothelial dysfunctionassociated with atherosclerosis and also been shows to show some promisein the impairment of carcinogenesis. Vitamin E has also been show todepress the decline in immune response, and thereby decrease theincidence of neoplasm's and infections in the aged. Vitamin E has beenshown to inhibit the growth of squamous cell carcinoma cells. It hasalso been suggested that Vitamin E levels man help determine the hostresistance to parasite and viral infections. There is also epidemologicevidence that Vitamin E may reduce the risk of coronary heart diseaseand may be effective in the treatment of dermatitis and may be effectivein combating tardive dyskinesia. Vitamin A has also been shown toprevent diabetes induced abnormal retinal blood flow. It has also beendemonstrated that Vitamin E can prevent the activation of protein kinaseC(PKC) and diacylglycerol (DAG) in blood vessels during hyperglycemiathus suppressing their negative effects on the vascular cells andtissues. Another study has shown that Vitamin E can slow the rate ofmotor decline in patients with Huntington's disease.

Vitamin K is an essential cofactor in the formation of a microsomalcarboxlase that is necessary in converting glutamyl residues in certainprotein precursors into gamma-carboxyglutamates which is required byclotting factors to cause clotting of blood. Vitamin K has also beenshown to play an important role in bone metabolism and can be used toprevent to loss of bone mass (osteoporosis). It has been reported thatVitamin K also displays antioxidant properties. Vitamin K may also beused as prophylaxis in high dose chemotherapy.

The amount of zinc oxide present in the therapeutic wound healingcompositions of the present invention is a therapeutically effectiveamount. A therapeutically effective amount of zinc oxide is that amountof zinc oxide necessary for the inventive composition to reduce injuryto mammalian cells or increase the resuscitation rate of injuredmammalian cells or the amount necessary to aid or cause theproliferation of new cells including precursor cells. The exact amountof zinc oxide is a matter of preference subject to such factors as typeof condition being treated as well as the other ingredients in thecomposition. In a preferred embodiment zinc oxide is present in thetherapeutic wound healing composition in an amount from about 0.01% toabout 75%, preferably about 2% to about 25% and more preferably about 5%to about 20%, by weigh of the therapeutic wound healing composition.

The amount of the fat soluble vitamins present in the therapeutic woundhealing compositions of the present invention is a therapeuticallyeffective amount. A therapeutic all effective amount of fat solublevitamins is the amount necessary to resuscitate and cause proliferationto injured mammalian cells. The exact amount of fat soluble vitamins isa matter of preference subject to such factors as the type of conditionbeing treated as well as other ingredients in the composition. In apreferred embodiment, the fat soluble vitamins are present in thetherapeutic wound healing composition in an amount from about 0.01% toabout 100%, preferably from about 0.05% to about 40%, and morepreferably from about 1% to about 35%, by weight of the therapeuticwound healing composition.

Antioxidants are substances which inhibit oxidation or suppressreactions promoted by oxygen or peroxides. Antioxidants, especiallylipid-soluble antioxidants, can be absorbed into the cellular membraneto neutralize oxygen radicals and thereby protect the membrane. Theantioxidants usefully in the present invention may be selected from thegroup consisting of all forms of Vitamin A (retinol), all forms ofVitamin.sub.2 (3,4-didehydroretinol), all forms of carotene such asAlpha-carotene, beta-carotene (beta, beta-carotene), gamma-carotene,delta-carotene, all forms of Vitamin C (D-ascorbic acid, L-ascorbicacid), all forms of tocopherol such as Vitamin E Alpha-tocopherol,3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltri-decyl)-2H-1-benzopyran-6-ol),beta-tocopherol, gamma-tocopherol, delta-tocopherol. tocoquinone,tocotrienol, and Vitamin E esters which readily undergo hydrolysis toVitamin E such as Vitamin E acetate and Vitamin E succinate andpharmaceutically acceptable Vitamin E salts such as Vitamin E phosphateprodrugs of Vitamin A, carotene, Vitamin C, and Vitamin E,pharmaceutically acceptable salts of Vitamin A, carotene, Vitamin C, andVitamin E, and the like, and mixtures thereof. Preferably, theantioxidant is selected from the group of lipid-soluble antioxidantsconsisting of Vitamin A, beta-carotene, Vitamin E, Vitamin E acetate,and mixtures thereof. More preferably, the antioxidant is Vitamin E orVitamin E acetate. Most preferably, the antioxidant is Vitamin Eacetate.

The amount of antioxidant present in the therapeutic wound healingcompositions of the present invention is a therapeutically effectiveamount. A therapeutically effective amount of antioxidant is that amountof antioxidant necessary for the inventive composition to prevent andreduce injury to mammalian cells or increase the resuscitation rate ofinjured mammalian cells. The exact amount of antioxidant is a matter ofpreference subject to such factors as the type of condition beingtreated as well as the other ingredients in the composition. In apreferred embodiment, the antioxidant is present in the therapeuticwound healing composition in an amount from about 0.1% to about 40%,preferably from about 0.2% to about 30%, and more preterably from about0.5% to about 20% by weight or the therapeutic wound healingcomposition.

In accord with the present invention, the therapeutic wound healingcompositions of Embodiment One (IA.-F) for treating mammalian cells maybe selected from the group consisting of:

-   (IA.)(a) zinc oxide; and-   (b) all forms and precursors of Vitamins A; and,-   (c) all forms and precursors of Vitamin D.-   (I.B) (a) zinc oxide; and-   (b) all forms and precursors of Vitamin A; and-   (c) all forms and precursors of Vitamin D;-   (d) all forms and precursors of Vitamin E.-   (I.C) (a) zinc oxide; and-   (b) all forms and precursors of Vitamin A; and-   (c) all forms and precursors of Vitamin D; and-   (d) all forms and precursors of Vitamin K.-   (I.D) (a) zinc oxide; and-   (b) all forms and precursors of Vitamin A; and-   (c) all forms and precursors of Vitamin D; and-   (d) all forms and precursors of Vitamin E; and-   (e) all forms and precursors of Vitamin K.-   (I.E) (a) all forms and precursors of Vitamin A; and-   (b) all forms and precursors of Vitamin D; and-   (c) all forms and precursors of Vitamin E.-   (I.F) (a) all forms and precursors of Vitamin A; and-   (b) all forms and precursors of Vitamin D; and-   (c) all forms and precursors of Vitamin E; and-   (d) all forms and precursors of Vitamin K.-   (I.G) (a) all forms and precursors of Vitamin A; and-   (b) all forms and precursor of Vitamin D; and-   (c) all forms and precursors of Vitamin K.

Throughout this disclosure, applicant will suggest various theories ormechanisms by which applicant believes the components in the therapeuticwound healing composition and the antibacterial agents and antifungalagents function together in an unexpected synergistic manner to preventand reduce injury to mammalian cells, increase the resuscitation rate ofinjured mammalian cells, and the proliferation of new cells. While theapplicant may offer various mechanisms to explain the present invention,applicant does not want to be bound by theory. These mechanisms andtheories are suggested to better understand the present invention butare not intended to limit the effective scope of the claims.

Accordingly the combination of ingredients set out in the aboveembodiments function together in an enhanced manner to prevent andreduce injury to mammalian cells and increase the resuscitation rate ofinjured mammalian cells and cause the proliferation of new cells. Thetherapeutic effects of the combination of the components in each of theabove embodiments is markedly greater than that expected by the mereaddition of the individual therapeutic components. Hence, applicant'stherapeutic wound healing composition for treating mammalian cells havethe ability to increase rates of cellular proliferation, increasecellular viability, increase cellular resistance to cytotoxic agents,and stop bleeding.

B. Methods for Making the Therapeutic Wound Healing Compositions ofEmbodiment One (I.A-G).

The present invention extends to methods of making the therapeutic woundhealing compositions of Embodiment One (A.A-G). In general, atherapeutic wound healing composition is made by forming an admixture ofthe components of the composition. In a first aspect of Embodiment One(I.A), a therapeutic wound healing composition is made by forming anadmixture of the components of a) zinc oxide b) Vitamin A and, c)Vitamin D. In a second aspect of Embodiment One (I.B), a therapeuticwound healing composition is made by forming an admixtures of a) zincoxide, b) Vitamin A, c) Vitamin D, and d) Vitamin E. In a third aspectof Embodiment One (I.C), a therapeutic wound healing composition is madeby forming an admixture of a) zinc oxide, b) Vitamin A, and c) VitaminD, and, d) Vitamin K. In the fourth aspect of Embodiment One (I.D), atherapeutic wound healing composition is made by forming an admixture ofa) zinc oxide, b) Vitamin A, c) Vitamin D, d) Vitamin E, and e) VitaminK. In the fifth aspect of Embodiment One (I.E), a therapeutic woundhealing composition is made by making an admixture of a) Vitamin A, b)Vitamin D, and c) Vitamin E. In a sixth aspect of Embodiment One (I.F),a therapeutic wound healing composition is made by forming an admixtureof a) Vitamin A, b) Vitamin D, c) Vitamin E, and d) Vitamin K. In aseventh aspect of Embodiment One (I.G), a therapeutic wound healingcomposition is made by forming an admixture of a) Vitamin A, b) VitaminD, and c) Vitamin K.

C. Methods for Employing the Wound Healing Compositions of EmbodimentOne (I.A).

The present invention extends to methods for employing the therapeuticwound healing compositions of Embodiment One (IA) in vivo and in vitro.In general, a therapeutic wound healing composition is employed bycontacting the therapeutic composition with mammalian cells.

In the first aspect of Embodiment One (I.A), the invention is directedto a method for preventing and reducing injury to mammalian cells, andincreasing the resuscitation rate of injured mammalian cells, whichcomprises the steps of (A) providing a therapeutic wound healingcomposition which comprises (a) zinc oxide and (b) all forms andprecursors of Vitamin A, and (c) all forms and precursors of Vitamin D,and (B) contacting the therapeutic wound healing composition with themammalian cells.

In the second aspect of Embodiment One (I.B), the invention is directedto a method of preventing and reducing injury to mammalian cells andincreasing the resuscitation rate of injured mammalian cells whichcomprises the steps of (A) providing a therapeutic wound healingcomposition which comprises (a) zinc oxide and, (b) all forms andprecursors of Vitamin A, (c) all forms and precursors of Vitamin D and,(c) all forms and precursors of Vitamin E and, (B) contacting thetherapeutic wound healing composition with the mammalian cells.

In the third aspect of Embodiment One (I.C) the invention is directed toa method of preventing and reducing injury to mammalian cells,increasing the resuscitation rate of injured mammalian cells, andcausing the flow of blood to decrease or cease at the wound site bycausing it to coagulate, which comprises the steps of (A) providing thethe therapeutic wound healing composition which comprises (a) zinc oxideand, (b) all forms and precursors of Vitamin A and, (c) all forms andprecursors of Vitamin D and, (d) all forms and precursors of Vitamin Kand, (B) contacting the therapeutic wound healing composition with themammalian cells.

In the fourth aspect of Embodiment One (I.D) the invention is directedto a method of preventing and reducing injury to mammalian cells,increasing the resuscitation rate of injured mammalian cells, improvingthe remodeling phase of wound healing in mammalian cells, and causingthe flow of blood to decrease or cease by causing it to coagulate at thewound site which comprises the steps of (A) providing the therapeuticWound healing composition which comprises (a) zinc oxide and, (b) allforms and precursors of Vitamin A and, (c) ail forms and precursors ofVitamin D and, (d) all forms and precursors of Vitamin E and, (e) allforms and precursors of Vitamin K and, (B) contacting the therapeuticwound healing composition with the mammalian cells.

In the fifth aspect of Embodiment One (I.E) the invention is directed toa method of preventing and reducing injury to mammalian cells,increasing the resuscitation rate of injured mammalian cells andimproving the remodeling phase of wound healing in mammalian cells,which comprises the steps of (A) providing the therapeutic wound healingcomposition which comprises (a) all forms and precursors of Vitamin Aand, (b) all forms and precursors of Vitamin D and, (c) all forms andprecursors of Vitamin E and, (B) contacting the therapeutic woundhealing composition with the mammalian cells.

In the sixth aspect of Embodiment One (I.F) the invention is directed toa method of preventing and reducing injury to mammalian cells,increasing the resuscitation rate of injured mammalian cells, improvingthe remodeling phase of wound healing in mammalian cells, and causingthe flow of blood to decrease or cease by causing it to coagulate at thewound site, which comprises the steps of (A) providing the therapeuticwound healing composition which comprises (a) all forms and precursorsof Vitamin A and, (b) all forms and precursors of Vitamin D and, (c) allforms and precursors of Vitamin E and, (d) all forms and precursors ofVitamin K and, (B) contacting the therapeutic wound healing compositionwith the mammalian cells.

In a seventh aspect of Embodiment One (I.G) the invention is directed toa method of preventing and reducing injury to mammalian cells,increasing the resuscitation rate of injured mammalian cells, andcausing the flow of blood to decrease or cease by causing it tocoagulate at the wound site, which comprises the steps of (A) providingthe therapeutic wound healing composition which comprises (a) all formsand precursors of Vitamin A and, (b) all forms and precursors of VitaminD and, (c) all forms and precursors of Vitamin K and, (B) contacting thetherapeutic wound healing composition with the mammalian cells.

In a preferred embodiment, the invention is directed to a method forhealing a wound in a mammal which comprises the steps of:

-   (A) providing a therapeutic wound healing composition (I.A) which    comprises:

(a) zinc oxide; and

(b) all forms and precursors of Vitamin A; and

(c) all forms and precursors of Vitamin D; and

-   (B) contacting the therapeutic wound healing composition with the    wound.

The types of wounds which may be healed using the wound healingcompositions of Embodiment One (I.A-G) of the present invention arethose which result from an injury which causes epidermal damage such asincisions, wounds in which the skin is broken by a cutting instrument,and lacerations, wounds by which the skin is broken by a blunt or dullinstrument, and wounds of the skin caused by friction. The therapeuticcompositions may also be used to treat dermatological disorders such asburns, Candidiasis and diaper rash, donor and receptor site wounds forskin transplants, ulcers (cutaneous, decubitus, venous stasis, sicklecell, and diabetic), psoriasis, skin rashes, and sunburn photo reactiveprocess, and second and third degree burns. The topical therapeuticcompositions may also be used orally in the form of a mouthwash or sprayto protect or accelerate the healing of oral tissue such as mouth sores,burns, surgical sites and ulcerations. The topical therapeuticcompositions may further be used in opthomological preparations to treatwounds such as those which result from corneal ulcers, radialkeratotomy,corneal transplants, epikaratophakia and other surgically induced woundsin the eye. The thermorectal therapeutic compositions may be used inanorectal creams and suppositories to treat such conditions as pruritus,and proctitis, anal fissures, and hemorrhoids. In a preferredembodiment, the therapeutic compositions are used to treat wounds suchas incisions and lacerations.

The wound healing compositions of Embodiment One (I.A-G) of the presentinvention may be utilized in topical products, ingestible products, andtissue culture medium to protect mammalian cells and increase theresuscitation rate of mammalian cells and enhance cell reproduction. Forexample, the therapeutic wound healing compositions may be used intopical skin care products to protect and increase the resuscitationrate of skin tissues such as in the treatment of various dermatologicaldisorders such as photo-aging and sunburn photo-reactive processes.Injury of skin can occur for a variety of reasons. Injury often occursto individuals who wash their hands often, to individuals who areexposed to stressful environmental conditions (overexposure to sunlightor chemical) or to the elderly or individuals with an underlyingdisease. The addition of the wound healing compositions to the presentinvention to a lotion provides a source of antioxidants to the skinwhich would protect the skin from the harmful effects of UV light,chemicals, and severe drying as well as healing the skin injured bythese sources. The wound healing compositions may also be used for thefollowing indications: a) Moisturizing and protecting; b) Healing drycracked skin; c) healing irritated skin such as diaper rash; d) Healingsevere dry skin due to other diseases (venous dermatitis); e) treatingpsoriasis and other hyperproliferative diseases; protecting skin from UVlight damage (antioxident skin replacement and cell reproduction);treating seborrheic conditions; and h) treating shaving wounds in anafter shave lotion.

The topical therapeutic wound healing compositions may also be used inthe form of a mouth wash or a spray to protect and accelerate thehealing of injured oral tissue such as mouth sores and burns. Thetopical therapeutic wound healing compositions may further be used inopthalmological preparations such as eye care products to neutralizehydrogen peroxide used in the cleaning of contact lenses. The topicaltherapeutic wound healing compositions may also be used in anorectalcreams and suppositories to treat such conditions as pruritus ani,procitis, anal fissures, and hemorrhoids. Initially as white blood cellsenter a wound site, the cells release oxygen radicals depleting theantioxidants at the wound site, thus impairing the healing process.Incorporating the wound healing compositions of the present inventioninto a wound healing formulation would facilitate healing by providingthe site with usable antioxidants, and zinc oxide and vitamins A and Dfor cell resuscitation and reproduction. The wound healing compositionscan be used for the following indications: a) Healing of cuts andscrapes; b) Burns; c) decubitus ulcers; d) bed sores, pressure ulcers;e) Fissures, Hemorrhoids; f) Used in combination with immunostimulators(stimulate healing in healing deficient mammals); g) Post surgicalwounds including P&A's; h) bandages; i) Diabetic ulcerations; j) venousulcerations; k) sickle cell ulcerations, and l) used in combination withwound cleansing agents. The wound healing compositions may also be usedin ingestible products and increase the resuscitation rate of erosions,stomach ulcers, and hemorrhages in the gastric mucosa. Other injestibletherapeutic products include: stroke medications; autoimmune diseasemedications; arthritis medications; ulcer medications: cancermedications (cytotoxic agents); heart medications to improve regionalventricultar function aid restore normal heart rate and pressurefunctions; lung medications to repair injured tissues; liver medicationto suppress lipogenesis of alcoholic origin and prevent hepaticsteatosis; kidney medication to suppress urinary calculi; detoxificationmedication to antagonize heavy metal poisoning, cyanide poisoning,sodium sulfide poisoning, other types of poisoning; and reduce andneutralize the production of oxygen radicals which produces tissueinjury, to protect and further enhance the resuscitation rate of theinjured mammalian cells. The therapeutic wound healing composition maybe used in injestible products to treat inflammatory diseases such ashepatitis, gastritis, colitis, esophagitis, arthritis, and pancreatitis.

The therapeutic wound healing compositions of the present invention mayalso be used in tissue culture media and organ transplant media toreduce and prevent injury to mammalian cells to and increase theresuscitation rate of injured mammalian cells. Tissue cultures andtransplant organs encounter reactive oxygen species generated in theculture media by the injured cells. Organs particularly susceptible tooxidative damage during transport and transplantation due to reperfusioninjury following ischemia are corneas, livers, hearts and kidneys. Thetherapeutic wound healing composition my be useful to abrobatereperfusion injury to such transplant organs as well as resuscitate andcause proliferation of cells.

In a specific embodiment, the invention is directed to a method forpreserving mammalian cells in a culture medium which comprises steps of:

(A) providing a therapeutic wound healing composition selected from thegroup consisting of:

(I.A.) (a) zinc oxide; and

-   -   (b) all forms and precursors of Vitamins A; and    -   (c) all forms and precursors of Vitamin D.

(I.B) (a) zinc oxide; and

-   -   (b) all forms and precursors of Vitamin A; and    -   (c) all forms and precursors of Vitamin D;    -   (d) all forms and precursors of Vitamin E.

(I.C) (a) zinc oxide; and

-   -   (b) all forms and precursors of Vitamin A; and    -   (c) all forms and precursors of Vitamin D; and    -   (d) all forms and precursors of Vitamin K.

(I.D) (a) zinc oxide; and

-   -   (b) all forms and precursors of Vitamin A; and    -   (c) all forms and precursors of Vitamin D; and    -   (d) all forms and precursors of Vitamin E; and    -   (e) all forms and precursors of Vitamin K.

(I.E) (a) all forms and precursors of Vitamin A; and

-   -   (b) all forms and precursors of Vitamin D; and    -   (c) all forms and precursors of Vitamin E.

(I.F) (a) all forms and precursors of Vitamin A; and

-   -   (b) all forms and precursors of Vitamin D; and    -   (c) all forms and precursors of Vitamin E; and    -   (d) all forms and precursors of Vitamin K.

(I.G) (a) all forms and precursors of Vitamin A; and

-   -   (b) all forms and precursor of Vitamin D; and    -   (c) all forms and precursors of Vitamin K;        (B) providing mammalian cells in a culture medium; and        (C) contacting the therapeutic wound healing composition from        step(A) with the mammalian cell in the culture medium from step        (B).        D. Formulations of the Therapeutic Wound Healing Compositions of        Embodiment One (I.A-G).

Once prepared, the inventive therapeutic wound healing compositions ofEmbodiment One (I.A-G) may be stored for future use or may be formulatedin effective amounts with pharmaceutically acceptable carriers toprovide a wide variety of pharmaceutical preparations. Examples ofpharmaceutically acceptable carriers are pharmaceutical appliances,topical vehicles (non-oral and oral) and ingestible vehicles.

Examples of pharmaceutical appliances are sutures, staples, gauze,bandages, burn dressings, artificial skins, liposome or micellformulations, microcapsules, aqueous vehicles for soaking gauzedressings, and the like, and mixtures thereof. Non-oral topicalcompositions employ non-oral topical vehicles, such as creams, gels,formulations, foams, ointments and sprays, salves, and films, which areintended to be applied to the skin or body cavity and are not intendedto be taken by mouth. Oral topical compositions employ oral vehicles,such as mouthwashes, rinses, oral sprays, suspensions, and dental gels,which are intended to be taken by mouth but are not intended to beingested. Ingestible compositions employ ingestible or partly ingestiblevehicles such as confectionery bulking agents which include hard andsoft confectionery such as lozenges, tablets, toffees, nougats,suspensions, chewy candies, and chewing gums.

In one form of the invention, the therapeutic wound healing compositionis incorporated into a pharmaceutical appliance which may be in the formof sutures, staples, gauze, bandages, burn dressings, artificial skins,liposome or micell formulations, microcapsules, aqueous vehicles forsoaking gauze dressings, and the like, and mixtures thereof. A varietyof traditional ingredients may optionally be included in thepharmaceutical composition in effective amounts such as buffers,preservatives, toxicity adjusting agents, antioxidants, polymers foradjusting viscosity or for use as extenders, and excipients, and thelike. Specific illustrative examples of such traditional ingredientsinclude acetate and borate buffers, thimerosal, sorbic acid, methyl andpropyl paraben and colorobutanol preservatives; sodium chloride andsugars to adjust the toxicity; and excipients such as manitol, lactoseand sucrose. Other conventional pharmaceutical additives known to thosehaving ordinary skill in the pharmaceutical arts may also be used in thepharmaceutical composition.

In accordance with this invention, therapeutically effective amounts ofthe therapeutic wound healing compositions of the present invention maybe employed in the pharmaceutical appliance. These amounts are readilydetermined by those skilled in the art without the need for undueexperimentation. The exact amount of therapeutic wound healingcomposition employed is subject to such factors as the type andconcentration of the therapeutic wound healing composition and the typeof pharmaceutical appliance employed. Thus, the amount of therapeuticwound healing composition will be varied in order to obtain the resultdesired in the final product and such variations are within thecapabilities of those skilled in the art without need for undueexperimentation. In a preferred embodiment, the pharmaceuticalcomposition will comprise the therapeutic wound healing composition inan amount from about 0.1% to about 100%, by weight of the pharmaceuticalcomposition. In a more preferred embodiment, the pharmaceuticalcomposition will comprise the therapeutic wound healing composition inan amount of about 0.1% to about 25%, by weight of the pharmaceuticalcomposition. In a most preferred embodiment, the pharmaceuticalcomposition will comprise the therapeutic wound healing composition inan amount of about 0.1% to about 15%, by weight of the pharmaceuticalcomposition.

The therapeutic wound healing composition may also be delivered by usingionophoresis.

The present invention extends to methods for making the pharmaceuticalcompositions. In general, a pharmaceutical composition is made bycontacting a therapeutically effective amount of a therapeutic woundhealing composition With the pharmaceutical appliance and the otheringredients of the final desired pharmaceutical composition. Thetherapeutic wound healing composition may be absorbed onto apharmaceutical appliance.

Other ingredients will usually be incorporated into the composition asdictated by the nature of the desired composition as well known by thosehaving ordinary skill in the art. The ultimate pharmaceuticalcompositions are readily prepared using methods generally known in thepharmaceutical arts.

In another form of the invention, the therapeutic wound healingcomposition is incorporated into a non-oral topical vehicle which may bein the form of a cream, gel, foam, ointment, spray, and the like.Typical non-toxic non-oral topical vehicles known in the pharmaceuticalarts may be used in the present invention. The preferred non-oraltopical vehicles are water and pharmaceutically acceptablewater-miscible organicsolvents such as ethyl alcohol, isoprophylalcohol, propylene glycol glycerin, and the like, and the mixtures ofthese solvents. Water-alcohol mixtures are particularly preferred andare generally employed in a weight ratio from about 1:1 to about 20:1,preferably from about 3:1 to about 20:1, and most preferably from about3:1 to about 10:1, respectively.

The non-oral topical therapeutic wound healing compositions may alsocontain conventional additives employed in those products. Conventionaladditives include humectants, emollients, lubricants, stabilizers, dyes,and perfumes, providing the additives do not interfere with thetherapeutic properties of the therapeutic wound healing composition.

The coloring agents (colors, colorants) useful in the non-oral topicaltherapeutic wound healing composition are used in amounts effective toproduce the desired color. These coloring agents include pigments whichmay be incorporated in amounts up to about 6% by weight of the non-oraltopical therapeutic wound healing composition. A preferred pigment,titanium dioxide may be incorporated in amounts up to about 2%, andpreferably less than about 1%, by weight of the non-oral topicaltherapeutic wound healing composition. The coloring agents may alsoinclude natural food colors and dyes suitable for food, drug andcosmetic applications. These coloring agents may also include naturalfood colors and dyes suitable for food, drug and cosmetic applications.These coloring agents are known as F.D.& C. dyes and lakes. Thematerials acceptable for the foregoing uses are preferablewater-soluble. Illustrative non limiting examples include the indigoiddye known as F.D.& C. Blue No. 2, which is the disodium salt of5,5-indigotindisulfonic acid. Similarly, the dye known as F.D.& C. GreenNo 1 comprises a triphenylmenthane dye and is the monosodium salt of4->4-(N-ethyl-p-sulfoniumbenzylamino)diphenylmenthylene!-1-(N-ethyl-N-p-sulfoniumbenzyl)delta-2,5-cyclohexadieneimine!. A full recitation of all F.D.& C. coloring agents and theircorresponding chemical structures may be found in the Kirk-OthmerEncyclopedia of Chemical Technology, 3rd Edition, in volume 5 at pages857-884, which text is incorporated herein by reference.

In accordance with this invention, therapeutically effective amounts ofthe therapeutic wound healing compositions of the present invention ma)be admixed with a non-oral topical vehicle to form a topical therapeuticwound healing composition. These amounts are readily determined by thoseskilled in the art without the need for undue experimentation. In apreferred embodiment the non-oral topical therapeutic wound healingcompositions will comprise the therapeutic wound healing composition inan amount from about 0.1% to about 10% and a non-oral topical vehicle ina quantity sufficient to bring the total amount of composition to 100%,by weight of the non-oral topical therapeutic wound healing composition.In a more preferred embodiment, the non-oral topical therapeutic woundhealing compositions will comprise the therapeutic wound healingcomposition in an amount from about 0.1% to about 5, and in mostpreferred embodiment, the non-oral topical therapeutic wound healingcompositions will comprise the therapeutic wound healing composition inan amount from about 0.1% to about 2%, and anon-oral topical vehicle ina quantity sufficient to bring the total amount of composition to 100%,by weight of the non-oral topical therapeutic wound healing composition.

The present invention extends to methods for preparing the non-oraltopical therapeutic wound healing compositions. In such a method, thenon-oral topical therapeutic wound healing composition is prepared byadmixing a therapeutically effective amount of the therapeutic woundhealing composition of the present invention and a non-topical vehicle.The final compositions are readily prepared using standard methods andapparatus generally known by those skilled in the pharmaceutical arts.The apparatus useful in accordance with the present invention comprisesmixing apparatus well known in the pharmaceutical arts, and thereforethe selection of to the specific apparatus will be apparent to theartisan.

In another form of the invention, the therapeutic wound healingcomposition is incorporated into an oral topical vehicle which may be inthe form of a mouthwash, rinse, oral spray, suspension, dental gel, andthe like. Typical nontoxic oral vehicles known in the pharmaceuticalarts may be used in the present invention the preferred oral vehiclesare water, ethanol, and water-ethanol mixtures. The water-ethanolmixtures are generally employed in a weight ratio from about 1:1 toabout 20:1, preferably from about 3:1 to about 20:1, and most preferablyfrom about 3:1 to about 10:1, respectively. The pH value of the oralvehicle is generality from about 4 to about 7, and preferably from about5 to about 6.5. An oral topical vehicle having a pH value below about 4is generally irritating to the oral cavity and an oral vehicle having apH value greater than about 7 generally results in an unpleasant mouthfeel.

The oral topical therapeutic wound healing compositions may also containconventional additives normally employed in those products. Conventionaladditives include fluorine providing compound, a sweetening agent, aflavoring agent, a coloring agent, a humectant, a buffer, and anemulsifier, providing the additives do not interfere with thetherapeutic properties of the therapeutic wound healing composition.

The coloring agents and humectants, and the amounts of these additivesto be employed, set out above as useful in the non-oral topicaltherapeutic wound healing composition may be used in the oral topicaltherapeutic wound healing composition.

Fluorine providing components may be fully or slightly water soluble andare characterized by their ability to release fluoride ions or fluoridecontaining ions in water and by their lack or reaction with othercomponents in the composition. Typical fluorine providing compounds areinorganic fluoride salts such as water-soluble alkali metal, and heavymetal salts, for example, sodium fluoride, potassium fluoride, ammoniumfluoride, cuprous fluoride, zinc fluoride stannic fluoride, stannousfluoride, barium fluoride, sodium fluorosilicate, ammoniumfluorosilicate, sodium fluorozirconate, sodium monofluocophosphate,aluminum mono-and-di-fluoride and monofluorophosphates, such as sodiumand stannous fluoride, sodium monofluorophospate and mixtures thereof,are preferred.

The amount of fluorine providing compound present in the present oraltopical therapeutic wound healing composition is dependent upon the typeof fluorine providing compound employed, the solubility of the fluorinecompound, and the nature of the final oral therapeutic wound healingcomposition. The amount of fluorine providing compound used must be anontoxic amount. In general, the fluorine providing when used will bepresent in an amount up to about 1%, preferably from about 0.001% toabout 0.1%, and most preferably from about 0.001% to about 0.1%, andmost preferably from about 0.001% to about 0.05%, by weight of the oraltopical therapeutic wound healing composition.

When sweetening agents (sweeteners) are used, those sweeteners wellknown in the art, including both natural and artificial sweeteners, maybe employed. The sweetening agent used may be selected from a wide rangeof materials including water-soluble sweetening agents, water-solubleartificial sweetening agents, water-soluble sweetening agents derivedfrom naturally occurring water-soluble sweetening agents, dipeptidebased sweetening agents, and protein based sweetening agents, includingmixtures thereof. Without being limited to particular sweetening agents,representative categories and examples include:

-   -   (a) water-soluble sweetening agents such as monosacchardes,        disaccharides and polysaccharides such as xylose, ribose,        glucose (dextrose), mannosse, galactose, fructose (levulose),        sucrose (sugar), maltose, invert sugar (a mixture of fructose        and glucose derived from sucrose), partially hydrolyzed starch,        corn syrup solids, dihydrochalcones, monellin, steviosides, and        glycyrrhizin, and mixtures thereof;    -   (b) water-soluble artificial sweeteners such as soluble        saccharin salts, i.e., sodium or calcium saccharin salts,        cyclamate salts the sodium, ammonium or calcium salt of 3,4        dihydro-6-methyl-1,2,3-oxatahizine-4-one-2-2-dioxide, the        potassium salt of        3,4-dihydro-6-methyl-1,2,3-oxathizine4-one-2,2-dioxide        (Acesufame-K), the free acid form of saccharin, and the like;    -   (c) dipeptide based sweeteners, such as L-aspartic acid derived        sweeteners, such as L-aspartyl-L-phenylalaunie methyl ester        (Aspartame) and materials describes in U.S. Pat. No. 3,492,131,        L-Alpha-aspartyl-N-(2,2,4,4-tetamethyl-3-theitanyl)-D-alanin-amide        hydrate (Altrame), methyl esters of L-aspartyl-L-phenylglycerine        and L-aspartyl-L-2-5dihydrophenyl-glycerine,        L-aspartyl-2,5dydro-L-phenylaanine;        L-aspartyl-L-(1-cyclohexen)-alanine, and the like;    -   (d) water-soluble sweeteners derived from naturally occurring        water-soluble sweeteners, such as chlorinated derivatives or        ordinary sugar (sucrose), e.g., chlorodexosugar derivatives such        as derivatives of chlorodeoxysucrose or        chlorodexoygalactosucrose, known, for example, under the product        designation of Sucrose: examples of chlorodexoysucrose and        chlorodeoxygalacto-sucrose derivatives include but not limited        to: 1-chloro-1′-dexoysucrose; 4-chloro-4-deoxy.    -   Alpha-D-galacto-pyranosyl-Alpha-D-fructofuranoside, or        4-chloro-4-deoxyalactosucrose;        4-chloro-4-deoxy-Alpha-D-galacto-pyroanosyl-1-chloro-1-deoxy-beta-D        fructo-furanoside, or 4,1′-dichloro4,1′-dideoxygalactosucrose;        1′, 6′-dichloro-1′,6′-dideoxysucrose;        4-chloro-4-deoxy-Alpha-D-galacto-pyranosyl-1,6-dichloro-1,6-dideoxy-.beta.-D-fructo-furanoside,        or 4,1′,6′-trichloro-4,1′,6′-trideoxygalacto-sucrose;        4,6-dichloro4,6-deoxy-Alpha-D-galacto-pyranosyl-6-chloro-6-deoxy-.beta.-D-fructofuranoside,        or 4,6,6′-trichloro4,6,6′-trideoxygalactosucrose;        6,1′,6′-trichloro-6,1′,6′-trideoxysucrose;        4,6-dichloro4,6-dideoxy-Alpha-D-galacto-pyranosyl-1,6dichloro-1,6-di-deoxy-.beta,-D-fructofuranoside,        or 4,6,1′,6′-tetrachloro4,6,1′,6′-tetradeoxygalacto-sucrose; and        4,6,1′,6′-tetrachloro-4,6,1′,6′-tetradeoxy-sucrose; and    -   (e) protein based sweeteners such as thaumaoccous danielli        (Thaumatin I and II).

In general, and effective amount of sweetening agent is utilized toprovide the level of sweetness desired in the particular oral topicaltherapeutic wound healing composition, and this amount will vary withthe sweetener selected and the final oral therapeutic product desired.The amount of sweetener normally present is in the range from about0.0025% to about 90%, by weight of the oral topical therapeutic woundhealing composition, depending upon the sweetener used. The exact rangeof amounts for each type of sweetener is well known in the art and isnot the subject of the present invention.

The flavoring agents (flavors, flavorants) which may be used includethose flavors known to the skilled artisan, such as natural andartificial flavors. Suitable flavoring agents include mints, such aspeppermint, citrus flavors such as orange and lemon, artificial vanilla,cinnamon, various fruit flavors, both individual and mixed, and thelike.

The amount of flavoring agent employed in the oral topical therapeuticwound healing composition is normally a matter of preference subject toSuch factors as the type of final oral therapeutic wound healingcomposition, the individual flavor employed, and the strength of flavordesired. Thus, the amount of flavoring may be varied in order to obtainthe result desired in the final product and such variations are withinthe capabilities of those skilled in the art without the need for undoexperimentation. The flavoring agents, when used, are generally utilizedin amounts that may, for example, range in amounts from about 0.05% toabout 6%, by weight of the oral topical therapeutic wound healingcomposition.

Suitable buffer solutions useful in the oral topical therapeutic woundhealing compositions include citric acid-sodium citrate solution,phosphoric acid-sodium acetate solution in amounts up to about 1%, andpreferably from about 0.05% to about 0.5% by weight of the oral topicaltherapeutic wound healing composition.

In accordance with this invention, therapetutically effective amounts ofthe therapeutic wound healing compositions of the present invention maybe admixed with an oral topical to vehicle to form a topical therapeuticwound healing composition. These amounts are readily determined by thoseskilled in the art without the need for undue experimentation. In apreferred embodiment, the oral topical therapeutic wound healingcompositions will comprise the therapeutic wound healing composition inan amount from about 0.1% to about 10% and a oral topical vehicle in aquantity sufficient to bring the total amount of composition to 100%, byweight of the oral topical therapeutic wound healing composition. In amore preferred embodiment, the oral topical therapeutic wound healingcomposition in an amount from about 0.1% to about 5%, and in a mostpreferred embodiment, the oral topical therapeutic wound Healingcompositions will comprise the therapeutic wound healing composition inan amount from about 0.1% to about 2%, and a oral topical vehicle inquantity sufficient to bring the total amount ot composition to 100%, byweight of the oral topical therapeutic wound healing composition.

The present invention extends to methods for preparing the oral topicaltherapeutic wound healing compositions. In such a method, the oraltopical therapeutic wound healing composition is prepared by admixing atherapeutically effective amount of the therapeutic wound healingcomposition of the present invention and an oral topical vehicle. Thefinal compositions are readily prepared using standard methods andapparatus generally known by those skilled in the pharmaceutical arts.The apparatus useful in accordance with the present invention comprisesmixing apparatus well known in the pharmaceutical arts, and thereforethe selection of the specific apparatus will be apparent to the artisan.

In a preferred embodiment, an oral topical therapeutic wound healingcomposition is made by first dissolving coloring agents, sweeteningagents, and similar additives in water. The therapeutic wound healingcomposition is then admixed with the aqueous solution. Then sufficientwater or ethanol, or mixtures of water and ethanol, are added to thesolution with mixing until the final solution volume is reached. In amore preferred embodiment, the therapeutic wound healing composition isadded to the solution as the final ingredient. The final oral topicaltherapeutic wound healing compositions are readily prepared usingmethods generally known in the pharmaceutical arts.

The oral therapeutic wound healing composition may also be in the formof dental gel. As used herein, the term “gel” means a solid or semisolidcolloid which contains considerable quantities of water. The colloidparticles in a gel are linked together in a coherent meshwork whichimmobilizes the water contained inside the meshwork.

The dental gel compositions of the present invention contain theconventional additives set out above for oral topical therapeutic woundhealing compositions such as mouthwashes, rinses, oral sprays, andsuspension and in addition, may contain additional additives such as apolishing agent, a desensitizing agent, and the like, providing theadditional additives do not interfere with the therapeutic properties ofthe therapeutic wound healing composition.

In a dental gel composition, the oral vehicle generally comprises water,typically in an amount from about 10% to about 90%, by weight of thedental gel composition. Polyethylene glycol, propylene glycol, glycerin,and mixtures thereof may also be present in the vehicle as humectants orbinders in amounts from about 18% to about 30%, by weight of the dentalgel composition. Particularly preferred oral vehicles comprise mixturesof water with polyethylene glycol or water with glycerin andpolypropylene glycol.

The dental gels of the present invention include a gelling agent(thickening agent) such as a natural or synthetic gum or gelatin.Gelling agents such as hydroxyethyl cellulose, methyl cellulose,glycerin, carboxypolymethylene, and gelatin and the like, and mixturesthereof may be used. The preferred gelling agent is hydroxyethylcellulose. Gelling agents may be used in amounts from about 0.5% toabout 5%, and preferably from about 0.5% to about 2%, by weight of thedental gel composition.

The dental gel compositions of the present invention may also include apolishing agent. In clear gels, a polishing agent of colloidal silicaand/or alkali metal aluminosilicate complexes is preferred since thesematerials have refractive indices close to the refractive indices of thegelling systems commonly used in dental gels. In non-clear gels,polishing agent of calcium carbonate or calcium dihydrate may be used.These polishing agents may be used in amounts up to about 75%, andpreferably in amounts up to about 50%, by weight of the dental gelcomposition.

The dental gel may also contain a desensitizing agent such as acombination of citric acid and sodium citrate. Citric acid may be usedin an amount from about 0.1% to about 3%, and preferably from about 0.2%to about 9%, and preferably from about 0.6% to about 3%, by weight ofthe dental gel composition.

In accordance with this invention, therapeutically effective amounts ofthe therapeutic wound healing compositions of the present invention maybe admixed into the dental gel compositions. These amounts are readilydetermined by those skilled in the art without the need for undueexperimentation. In a preferred embodiment, the dental gel compositionswill comprise the therapeutic wound healing composition in an amountfrom about 0.1% to about 10% and an oral topical vehicle in a quantitysufficient to bring the total amount of composition to 100%, by weightof the dental gel composition. In a more preferred embodiment, thedental gel compositions will comprise the therapeutic wound healingcomposition in an amount from abut 0.1% to about 5%, and in mostpreferred embodiment, the dental gel compositions will comprise thetherapeutic wound healing dental gel compositions in an amount fromabout 0.1% to about 2%, and an oral topical vehicle in a quantitysufficient to bring the total amount of composition to 100%, by weightof the dental gel composition.

The present invention extends to methods for preparing the therapeuticdental gel compositions. In such a method, the dental gel composition isprepared by admixing a therapeutically effective amount of thetherapeutic wound healing composition of the present invention and anoral topical vehicle. The final compositions are readily prepared usingmethods generally known by those skilled in the dental andpharmaceutical arts. The apparatus useful in accordance with the presentinvention comprises mixing apparatus well known in the pharmaceuticalarts, and therefore the selection of the specific apparatus will beapparent to the artisan.

In a preferred embodiment, a therapeutic dental gel composition is madeby first dispersing a gelling agent in a humectant or water, or amixture of both, the admixing to the dispersion an aqueous solution ofthe water-soluble additives such as the fluorine providing compound,sweeteners and the like, then adding the polishing agent, and lastlyadmixing the flavoring agent and the therapeutic wound healingcomposition the final gel mixture is then tubed or otherwise packaged.The liquids and solids in a gel product are proportioned to form acreamy or gelled mass which is extrudable from a pressurized containeror from a collapsible tube. The final therapeutic Bound healingcompositions are readily prepared using methods generally known in thepharmaceutical arts.

In yet another form of the invention, the therapeutic wound healingcomposition is incorporated into an ingestible vehicle. The ingestiblevehicle may be confectionery bulking agent in the form of lozenges,tablets, toffees, nougats, suspensions, chewy candies, chewing gums, andthe like. The pharmaceutically acceptable carriers may be prepared froma wide range of materials including, but not limited to, diluents,binders and adhesives, lubricants, disintegrants, coloring agentsbulking agents, flavoring agents, sweetening agents and miscellaneousmaterials such as buffers and absorbents that may be needed in order toprepare a particular therapeutic confection.

The preparation of confectionery formulation is historically well knownand has changes little through the years. Confectionery items have beenclassified as either “hard” confectionery or “soft” confectionery. Thetherapeutic wound healing compositions of the present invention can beincorporated into confectionery compositions by admixing the inventivecomposition into conventional hard and soft confections.

As used herein, the term confectionery material means a productcontaining a bulking agent selected from a wide variety of materialssuch as sugar, corn syrup, and in the case of sugarless bulling agents,sugar alcohols such as sorbitol and mannitol and mixtures thereof.Confectionery material may include such exemplary substances aslozenges, tablets, toffee, nougat, suspensions, chewy candy, chewing gumand the like. The bulking agent is present in a quantity sufficient tobring the total amount of composition to 100%. In general the bulkingagent will be present in amounts up to about 99.98%, preferably inamounts up to about 99.9%, and more preferably in amounts up to about99%, by weight of the ingestible therapeutic wound healing composition.

Lozenges are flavored medicated dosages forms intended to be sucked andheld in the mouth. Lozenges nay be in the form of various shapes such asflat, circular, octogonal and biconvex forms. The lozenge bases aregenerally in two forms: hard boiled candy and compressed tabletlozenges.

Hard boiled candy lozenges may be processed and formulated byconventional means. In general, a hard boiled candy lozenge has a basecomposed of a mixture of sugar and other carbohydrate bulking agentskept in an amorphous or glassy condition. This amorphous or glassy formis considered a solid syrup of sugar generally having from about 0.5% toabout 1.5% moisture. Such materials normally contain up to about 92%corn syrup, up to about 55% sugar and from about 0.1% to about 5% water,by weight of the final composition. The syrup component is generallyprepared from corn syrups high in fructose, but may include othermaterials. Further ingredients such as flavoring agents, sweeteningagents, acidulants, coloring agents and the like may also be added.

Boiled candy lozenges may also be prepared from non-fermentable sugarssuch as sorbitol, mannitol, and hydrogenated corn syrup. Typicalhydrogenated corn syrups are Lycasin, a commercially available productmanufactured by Roquette Corporation, and Hystar, a commerciallyavailable product manufactured by Lonza, Inc. The candy lozenges maycontain up to about 95% sorbitol, a mixture of sorbitol and mannitol ina ratio from about 9.5:0.5 up to about 7.5:2.5, and hydrogenated cornsyrup up to about 55%, by weight of the solid syrup component.

Boiled candy lozenges may be routinely prepared by conventional methodssuch as those involving, fire cookers, vacuum cookers, andscraped-surface cookers also referred to as high speed atmosphericcookers.

Fire cookers involve the traditional method of making a boiled candylozenge base. In this method, the desired quantity or carbohydratebulking agent is dissolved in water by heating the agent in kettle untilthe bulking agent dissolves. Additional bulking agent may be added andcooking continued until a final temperature of 145, degree. C. to 156,degree. C. is achieved. The batch is then cooled and worked as aplastic-like mass to incorporate additives such as flavors, colorantsand the like.

A high-speed atmospheric cooker uses a heat-exchanger surface whichinvolves spreading a film of candy on a heat exchange surface, the candyis heated to 165 .degree. C. to 170 .degree C. in a few minutes. Thecandy is then rapidly cooled to 100 .degree. C. to 120 degree. C. andworked as a plastic-like mass enabling incorporation of the additives,such as flavors, colorants and the like.

In vacuum cookers, the carbohydrate bulking agent is boiled to125.degree. C. to 132.degree. C., vacuum is applied and additional wateris boiled off without extra heating. When cooking is complete, the massis a semi-solid and has a plastic-like consistency. At this point,flavors, colorants, and other additives are admixed in the mass byroutine mechanical mixing operations.

The optimum mixing required to uniformly mix the flavoring agents,coloring agents and other additives during conventional manufacturing ofboiled candy lozenges is determined by the time needed to obtain auniform distribution of the materials. Normally, mixing times of from 4to 10 minutes have been found to be acceptable.

Once the boiled candy lozenge has been properly tempered, it may be cutinto workable portions or formed into desired shapes. A variety offorming techniques may be utilized depending upon the shape and size ofthe final product desired. A general discussion of the composition andpreparation of hard confections may be found in H. A. Liberian,Pharmaceutical Dosage Forms: Tablets, Volume I (1980), Marvel Decker,Inc., New York, N.Y. at pages 339 to 469, which disclosure isincorporated herein by reference.

The apparatus useful in with the present invention comprises cooking andmixing apparatus well known in the confectionery manufacturing arts, andtherefore the selection of the specific apparatus will be apparent tothe artisan.

In contrast, compressed tablet confections contain particulate materialsand are formed into structured under pressure. These confectionsgenerally contain sugars in amounts up to about 95%, by weighlt of thecomposition, and typical tablet excipients such as binders andlubricants as well as flavoring agents, coloring agents and the like.

In addition to hard confectionery materials, the lozenges of the presentinvention may be made of soft confectionery materials such as thosecontained in nougat. The preparation of soft confections, such asnougat, involves conventional methods, such as the combination of twoprimary components namely (1) high boiling syrup such as a corn syrup,hydrogenated starch hydorlysate or the like, and (2) a relatively lighttextured frappe, generally prepared from egg albumin, gelatin, vegetableproteins, such as soy derived compounds, sugarless milk derivedcompounds such as milk proteins, and mixtures thereof. The frappe isgenerally relatively light, and may, for example, range in density fromabout 0.5 to about 0.7 grams/cc.

The high boiling syrup, or “bob syrup” of the soft confectionery isrelatively viscous and has a higher density that the frappe component,and frequently contains a substantial amount of carbohydrate bulkingagent such as a hydrogenated starch hydrolysate. Conventionally, thefinal nougat composition is prepared by the addition of the “bob syrup”to the frappe under agitation, to form the basic nougat mixture. Furtheringredients such as flavoring agents, additional carbohydrate bullingagent, coloring agents, preservatives, medicaments, mixtures thereof andthe like may be added thereafter also under agitation. A generaldiscussion of the composition and preparation of nougat confections maybe found in B. W. Minifie, Chocolate, Cocoa and Confectionery; Scienceand Technology, 2nd edition, AVI Publishing Co., Inc., Westport, Conn.(1980), at pages 424-425, which disclosure is incorporated herein byreference.

The procedure for preparing the soft confectionery involves knownprocedures. In general, the frappe component is prepared first andthereafter the syrup component is slowly added under agitation at thetemperature of at least about 65.degree. C., and preferably at leastabout 100.degree C. The mixture of components is continued to be mixedto form a uniform mixture, after which the mixture is cooled to atemperature below 80.degree. C., at which point, the flavoring agent maybe added. The mixture is further mixed for an additional period until itis ready to be removed and formed into suitable confectionery shapes.

The ingestible therapeutic wound healing compositions may also be in theform of a pharmaceutical suspension. Pharmaceutical suspensions of thisinvention may be prepared by conventional methods long established inthe art of pharmaceutical compounding. Suspensions may contain adjunetmaterials employed in formulating the suspensions of the art. Thesuspensions of the present invention can comprise:

(a) preservatives such as butylated hydroyanisole (BHA), butylatedhydroxytoluene (BHr), benzoic acid, ascorbic acid, methyl paraben,propyl paraben, tocopherols, and the like, and mixtures thereof.Preservatives are generally present in amounts up to about 1%, andpreferably from about 0.05% to about 0.5%, by weight of the suspension;

(b) buffers Such as citric acid-sodium citrate, phosphoric acid-sodiumphosphate, and acetic acid-sodium acetate in amounts up to about 1%, andpreferably from about 0.05% to about 0.5%, by weight of the suspension;

(c) suspending agents or thickeners such as cellulosics likemethylcellulose, carregeenans like alginic acid and its derivatives,xanthan gums, gelatin, acacias, and microcrystalline cellulose inamounts up to about 20%, and preferably from about 1% to about 15%, byweight of the suspension;

(d) antifoaming agents such as dimethyl polysiloxane in amounts up toabout 0.2%, and preferably from about 0.01% to about 0.1%, by weight ofthe suspension;

(e) sweeteining agents such as those sweeteners well known in the art,including both natural and artificial sweeteners. Sweetening agents suchas monosaccharides, disaccharides and polyaccharides such as xylose,ribose, glucose (dextrose), mannose, galactoser, fructose Oevulose),sucrose (sugar), maltose, invert sugar (a mixture of fructose andglucose derived from sucrose), partially hydrolyzed starch, corn syrupsolids, dihydrochalcones, monellin, steviosides, glycyrrhizin, and sugaralcohols such as sorbitol, mannitol, maltitol, hydrogenated starchhydrolysates and mixtures thereof may be utilized in amounts up to about60%, and preferably from about 20% to about 50%, by weight of thesuspension. Water-soluble artificial sweeteners such as solublesaccharin salts, i.e., sodium or calcium saccharinoxathiazine4-one-2-2-dioxide, the potassium salt of3,4-dihydro-6-methyl-1,2,3-oxathiazine4-one-2,2-ioxide (Acesulfame-K),the free acid form of saccharin, and the like may be utilized in amountsfrom about 0.001 to about 5%, by weight of the suspension;

(f) flavoring agents such as those flavors well known to the skilledartisan, such as natural and artificial flavors and mints, such aspeppermint, menthol, citrus flavors such as orange and lemon, artificialvanilla, cinnamon, various fruit flavors, both individual and mixed andthe like may be utilized in amounts from about 0.5% to about 5%, byweight of the suspension;

(g) coloring agents such as pigments which may be incorporated inamounts up to about 6%, by weight of the suspension. A preferredpigment, titanium dioxide, may be incorporated in amounts up to about2%, and preferably less than about 1%, by weight of the suspension. Thecoloring agents may also include natural food colors and dyes suitablefor food, drug and cosmetic applications. These colorants are known asF.D.& C. dyes and lakes. The materials acceptable for the foregoing usesare preferably water-soluble. Such dyes are generally present in amountsup to about 0.25%, and preferably from about 0.05% to about 0.2%, byweight of the suspension;

(h) decolorizing agents such as sodium metabisulfite, ascorbic acid andthe like may be incorporated into the suspension to prevent colorchanges due to aging. In general, decolorizing agents may be used inamounts up to about 0.25%, and preferably from about 0.05% to about0.2%, by weight of the suspension; and

(i) solubilizers such as alcohol, propylene glycol, polyethylene glycol,and the like may be used to solubilize the flavoring agents. In general,solubilizing agents may be used in amounts up to about 10% andpreferably from about 2% to about 5%, by weight of the suspension.

The pharmaceutical suspensions of the present invention may be preparedas follows:

(A) admix the thickener with water heated from about 40° C. to about 95°C., preferably from about 40° C. to about 70° C., to form a dispersionif the thickener is not water soluble or a solution if the thickener iswater soluble;

(B) admix the sweetening agent with water to form a solution;

(C) admix the therapeutic wound healing composition with thethickener-water admixture to form a uniform thickener-therapeutic woundhealing composition;

(D) combine the sweetener solution with the thickener-therapeutic woundhealing composition and mix until uniform; and

(E) admix the optional adjunct materials such as coloring agents,flavoring agents, decolorants, solubilizers, antifoaming agents, buffersand additional water with the mixture of step (D) to form thesuspension.

The ingestible therapeutic wound healing compositions of this inventionmay also be in chewable form to achieve acceptable stability and qualityas well as good taste and mouth feel in a chewable formulation severalconsiderations are important. These considerations include the amount ofactive substance per tablet, the flavoring agent employed, the degree ofcompressibility of the tablet and the organoleptic properties of thecomposition.

Chewable therapeutic candy is prepared by procedures similar to thoseused to make soft confectionery. In a typical procedure, a boiledsugar-corn syrup blend is formed to which is added a frappe mixture. Theboiled sugar-corn syrup blend may be prepared from sugar and corn syrupblended in parts by weight ration of about 90:10 to about 10:90. Thesugar-corn syrup blend is heated to temperatures above about 120.degree.C. to remove water and to form a molten mass. The frappe is generallyprepared from gelatin, egg albumin, milk proteins such as casein, andvegetable proteins such as soy protein, and the like, which is added toa gelatin solution and rapidly mixed at ambient temperature to form anaerated sponge like mass. The frappe is then added to the molten candymass and mixed until homogeneous at temperatures between about65.degree. C. and about 120.degree. C.

The ingestible therapeutic wound healing composition of the instantinvention can then be added to the homogeneous mixture as thetemperature is lowered to about 65.degree. C.−95.degree. C. whereuponadditional ingredients can then be added such as flavoring agents andcoloring agents. The formulation is further cooled and formed intopieces of desired dimensions.

A general discussion of the lozenge and chewable tablet forms ofconfectionery may be found in H. A. Lieberman and L. Lachmaan,Pharmaceutical Dosage Forms: Tablets Volume 1, Marcel Dekker, Inc., NewYork, N.Y. at pages 289 to 466, which disclosure is incorporated hereinby reference.

In accordance with this invention, therapeutically effective amounts ofthe therapeutic no wound healing compositions of the present inventionmay be admixed into the hard and soft confectionery products. Theseamounts are readily determined by those skilled in the art without theneed for undue experimentation. In a preferred embodiment, theingestible therapeutic wound healing composition will comprise thetherapeutic wound healing composition in an amount from about 0.01% toabout 10%, and an ingestible vehicle, that is a pharmaceuticallyacceptable carrier, in a quantity sufficient to bring the total amountof composition to 100%; by weight the ingestible therapeutic woundhealing composition. In a more preferred composition will comprise thetherapeutic wound healing composition in an amount from about 0.1% toabout 5%, and in a most preferred embodiment, the ingestible compositionwill comprise the therapeutic wound healing composition in an amountfrom about 0.01% to about 2%, and an ingestible vehicle in a quantitysufficient to bring the total amount of composition to 100%, by weightthe ingestible therapeutic wound healing composition.

The present invention extends to methods of making the ingestibletherapeutic wound healing compositions. In such methods, an ingestibletherapeutic wound healing composition is prepared by admixing atherapeutically effective amount of the therapeutic wound healingcomposition with a pharmaceutically-acceptable carrier. The apparatususeful in accordance with the present invention comprises mixing andheating apparatus well known in the confectionery arts, and thereforethe selection of the specific apparatus will be apparent to the artisan.The final ingestible therapeutic wound healing compositions are readilyprepared using methods generally known in the confectionery arts.

The therapeutic wound healing compositions man also be incorporated intochewing gums. In this form of the invention, the chewing gum compositioncontains a gum base, a bulking agent, the inventive therapeutic woundhealing composition, and various additives.

The gum base employed will vary greatly depending upon various factorssuch as the type of base desired, the consistency of gum desired and theother components used in the composition to make the final chewing gumproduct. The gum base may be any water-insoluble gum base known in theart, and includes those gum bases utilized for chewing gums and bubblegums. Illustrative examples of suitable polymers in gum bases includeboth natural and synthetic elastomers and rubbers. For example, thosesuch as chicle, crown gum, nispero, rosadinha, jelutong, perillo, nigergutta, tunu, balatsa, gutta-ercha, lechi-capsi, sorva, gutta kay,mixtures thereof and the like. Synthetic elastomers such asbutadiene-styrene copolymers, ployisobutylene isobutylene-isoprenecopolymers, polyethylene, mixtures thereof and the like are particularlyuseful.

The gum base may include a nontoxic vinyl polymer, such as polyvinylacetate and its partial hydrolysate, polyvinyl alcohol, and mixturesthereof. When utilized, the molecular weight of the vinyl polymer mayrange from about 2,000 up to and including about 94,000.

The amount of gum base employed will vary greatly depending upon variousfactors such as the type of base used, the consistency of the gumdesired and the other components used in the composition to make thefinal chewing gum product. In general, the gum base will be present inamounts from about 5% to about 94%, by weight of the final chewing gumcomposition, and preferably in amounts from about 15% to about 45%, andmore preferably in amounts from about 15% to abut 35%, and mostpreferably in amounts from about 20% to about 30%, by weight of thefinal chewing gum composition.

The gum base composition may contain conventional elastomer solvents toaid in softening the elastomer base component. Such elastomer solventsmay comprise terpinene resins such as polymers of Alpha-pinene or.beta.-pinene, methyl, glycerol or pentaerythritol esters of rosins ormodified rosins and gums, such as hydrogenated, dinierized orpolymerized rosins or mixtures thereof. Examples of elastomers solventssuitable for use herein include the pentaerythritol ester of partiallyhydrogenated wood or gum rosin, the pentaerydiritol ester of wood or gumrosin, the glycerol ester of polymerized wood rosin, the glycerol esterof partially dimerized wood or gum rosin, the glycerol ester of tall oilrosin, the glycerol ester of wood or gum rosin and the partiallyhydrogenated wood or gum rosin and the partially hydrogenated methylester of wood or rosin, mixtures thereof, and the like. The elastomersolvent may be employed in amounts from about 5% to about 75%, by weightof the gum base, and preferably from about 45% to aibout 70%, by weightof the gum base.

A variety of traditional ingredients may be included in the gum base ineffective amounts such as plasticizers or softeners such as lanolin,palmitic acid, oleic acid, stearic acid, sodium stearate, potassiumstearate, glycerin triacetate, glyceryl lecithin, glyceryl monostearate,polylene glycol monostearate, acetylated monoglyceride, glycerine,mixture thereof, and the like may also be incorporated into the gum baseto obtain a variety of desirable textures and consistency properties.Waxes for example, natural and synthetic waxes, hydrogenated vegetableoils petroleum waxes such as polyurethane waxes, polyethylene waxes,paraffin waxes, microcrystallin waxes fatty waxes, sorbitanmonostearate, tallow, propylene glycol, mixtures thereof, and the likemay also be incorporated into the gum base to obtain a variety ofdesirable textures and consistency properties. These traditionaladditional materials are generally employed in amounts up to about 30%,by weight of the gum base, and preferably in amounts from about 3% toabout 20%, by weight of the gum base.

The gum base may include effective amounts of mineral adjuvants such ascalcium carbonate, magnesium carbonate, alumina, aluminum hydroxide,aluminum silicate, talc, tricalcium phosphate, dicalcium phosphate andthe like as well as mixtures thereof. These mineral adjuvants may serveas fillers and textaral agents. These fillers or adjuvants may be usedin the gum base in various amounts. Preferably the amount of filler whenused will be present in an amount up to about 60%, by weight of thechewing gum base.

The chewing, gum base may additionally include the conventionaladditives of coloring agents, antioxidants, preservatives and the likefor example, titanium dioxide and other dyes suitable for food, drug andcosmetic applications, known as F.D. & C dyes, may be utilized. Anantioxidant such as butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), propyl gallate, and mixtures thereof may also beincluded. Other conventional chewing gum additives known to one havingordinary skill in the chewing gum are may also be used in the chewinggum base.

The gum composition may include effective amounts of conventionaladditives selected from the group consisting of sweetening agents(sweeteners), plasticizers, softeners, emulsifiers, waxes, fillers,bulking agents, mineral adjuvants, flavoring agents (flavors,flavorings), coloring agents (colorants colorings), antioxidants,acidulants, thickeners, mixtures thereof and the like. Some of theseadditives may serve more than one purpose. For example, in sugarless gumcompositions, the sweetener, e.g., sorbitol other sugar alcohol ormixture thereof, may also function as a bulking agent. Similarly, insugar containing gum compositions, the sugar sweetener can also functionas a bulking agent.

The plasticizers, softeners, mineral adjuvants, colorants, waxes andantioxidants discussed above as being suitable for use in the gum basemay also be used in the gum composition. Examples of other conventionaladditives which may be used include emulsifiers, such as lecithin andglyceryl monostearate, thickeners, used alone or in combination withother softeners, such as methyl cellulose, alginates, carrageenan,xanthan gum, gelatin, carob, tragacanth, locust bean, and carboxymethyl, cellulose, acidulants such as malic acid, adipic acid, citricacid, tartaric acid, fumaric acid, and mixtures thereof, and fillers,such as those discussed about under the category of mineral adjuvants.The fillers when used may be utilized in an amount up to about 60%, byweight of the gum composition.

Bulking agents (carriers, extenders) suitable for use in chewing gumsinclude sweetening agents selected from the group consisting ofmonosaccharides, disaccharides, poly-saccharides, sugar alcohols, andmixtures thereof; polydextrose; maltodextrins; miners, such as calciumcarbonate, talc, titanium dioxide, dicalcium phosphate, and the like.Bulking agents may be used in amounts up to about 90%, by weight of thefinal gum composition, with amounts from about 40% to about 70% weightof the gum composition being preferred, with from about 50% to about65%, by weight, being more preferred and from about 55% to about 60%, byweight of the chewing gum composition being most preferred.

The sweetening agent used may be selected from a wide range of materialsincluding water-soluble sweeteners, water-soluble artificial sweeteners,water-soluble sweeteners derived from naturally occurring water-solublesweeteners, dipeptide based sweeteners, and protein based sweeteners,including mixtures thereof. Without being limited to particularsweeteners, representative categories and examples include:

(a) water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides suck as xylose, ribulose, glucose(dextrose), mannose, galactose, fructose (evulose), sucrose (sugar),maltose, invert sugar (a mixture of fructose and glucose derived fromsucrose), partially hydrolyzed starch, corn syrup solids,dihydrochalcones, monellin, steviosides, glycyrrhizin, and sugaralcohols such as sorbitol, mannitol, maltitol, hydrogenated starchhydrolysates and mixtures thereof;

(b) water-soluble artificial sweeteners such as soluble-saccharin salts,i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium,ammonium or calcium salt of3,4-dihydro-6-methyl-1,2,3oxathiazine-4one-2,2-dioxide, the potassiumsalt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-ioxide(Acesulfame-K), the free acid form of saccharin, and the like;

(c) dipeptide based sweeteners, such as L-aspartic acid derivedsweeteners, such as L-aspartyl-Lphenylalanine methyl ester (Aspartame)and the materials described in U.S. Pat. No. 3,492,131L-Alpha-aspartyl-N-(22,2,4,4-tetramethyl-3-thietanyl)-D-alanin-amidehydrate (Alitame), methyl esters of -aspartyl-L-phenylglycerine andL-aspartyl-L-(1-cyclohexen)-alanine, and the like.

(d) water-soluble sweeteners derived from naturally occurringwater-soluble sweeteners, such as chlorinated derivatives or ordinarysugar (sucrose), known, for example, under the product designation ofSucralose; and

(e) protein based sweeteners such as thaumaoccous danielli (Thaumatin Iand II). In general, an effective amount of sweetener is utilized toprovide the level of bulk and/or sweetness desired, and this amount willvary with the sweetener selected this amount of sweetener will normallybe present in amounts from about 0.0025% to about 90%, by weight of thegum composition, depending upon the sweetener used. The exact range ofamounts for each type of sweetener is well known in the art and is notthe subject of the present invention the amount of sweetener ordinarilynecessary to achieve the desired level of sweetness is independent fromthe flavor level achieved from flavor oils.

Preferred sugar based-sweeteners are sugar (sucrose), corn syrup andmixtures thereof. Preferred sugarless sweeteners are the sugar alcohols,artificial sweeteners, dipeptide based sweeteners and mixtures thereof.Preferably, sugar alcohols are used in the sugarless compositionsbecause these sweeteners can by used in amounts which are sufficient toprovide bulk as well as the desired level of sweetness. Preferred sugaralcohols are selected from the group consisting of sorbitol, xylitol,maltitol, mannitol, and mixtures thereof. More preferably, sorbitol or amixture of sorbitol and mannitol is utilized. The gamma form of sorbitolis preferred, an artificial sweetener or dipeptide based sweetener ispreferably added to the gum compositions which contain sugar alcohols.

The coloring agents useful in the gum compositions are used in amountseffective to produce the desired color. These coloring agents includepigments which may be incorporated in amounts up to about 6% by weightof the gum composition. A preferred pigment, titanium dioxide, may beincorporated in amounts up to about 2%, and preferably less than about1% by weight of the composition. The colorants may also include naturalfood colors and dyes suitable for food, drug and cosmetic applications.These colorants are known as F.D. & C. dyes and lakes. The materialsacceptable for the foregoing uses are preferably water-soluble.Illustrative nonlimiting examples include the indigoid dye known asF.D.& C. Blue No. 2, which is the disodium salt of5,5-indigotidisulfonic acid. Similarly, the dye known as F.D.& C. GreenNo. 1 comprises a triphenylmethane dye and is the monosodium salt of4->4-(N-ethyl-p-sulfoniumbenzylamino)diphenylmethylene!->1-(N-ethyl-N-p-sulfomumbenzyl)-delta-2,5-cyclohexadienimine!.A full recitation of all F.D.& C. colorants and their correspondingchemical structures may be found in the Kirk-Othmer Encyclopedia ofChemical Technology, 3rd Edition, in volume 5 at pages 857-884, whichtext is incorporated herein by reference.

Suitable oils and fats usable in gum compositions include partiallyhydrogenated vegetable or animal fats, such as coconut oil, palm kerneloil, beef tallow, lard, and the like. These ingredients when used aregenerally present in amounts up to about 7%, by weight, and preferablyup to about 3.5%, by weight of the gum composition.

In accordance with this invention, therapeutically effective amounts ofthe therapeutic wound healing compositions of the present invention maybe admixed into a chewing gum. These amounts are readily determined bythose skilled in the art without the need for undue experimentation. Ina preferred embodiment, the final chewing gum composition will comprisethe therapeutic wound healing composition in an amount from about 0.1%to about 10% and a chewing gum composition in a quantity sufficient tobring the total amount of composition to 100%, by weight of the chewinggum composition. In a more preferred embodiment, the final chewing gumcomposition will comprise the therapeutic wound healing composition inan amount from about 0.1% to about 5%, and in a most preferredembodiment, the final chewing gum composition will comprise thetherapeutic wound healing composition in an amount from about 0.1% toabout 2%, and a chewing gum composition in a quantity sufficient tobring the total amount of composition to 100%, by weight of the chewinggum composition.

The present invention extends to methods of making the therapeuticchewing gum compositions the therapeutic wound healing compositions maybe incorporated into an otherwise conventional chewing gum compositionusing standard techniques and equipment known to those skilled in theart. The apparatus useful in accordance with the present inventioncomprises mixing and heating apparatus well known in the chewing gummanufacturing arts, and therefore the selection of the specificapparatus will be apparent to the artisan.

For example, a gum base is heated to a temperature sufficiently highenough to soften the base without adversely effecting the physical andchemical make up of the base. The optimum temperatures utilized may varydepending upon the composition of the gum base used, but suchtemperatures are readily determined by those skilled in the art withoutundue experimentation.

The gum base is conventionally melted at temperatures that range fromabout 60° C. to about 120° C. for a period of time sufficient to renderthe base molten. For example, the gum base may be heated under theseconditions for a period of about thirty minutes just prior to beingadmired incrementally with the remaining ingredients of the base such asthe plasticizer, fillers, the bulking agent and/or sweeteners, thesoftener and coloring agents to plasticize the blend as well as tomodulate the hardness, viscoelasticity and formability of the base. Thechewing gum base is then blended with the therapeutic wound healingcomposition of the present invention which may have been previouslyblended with other traditional ingredients. Thereafter the gumcomposition mixture may be formed into desirable chewing gum shapes.

In a specific embodiment, the invention is directed to a therapeuticpharmaceutical composition for pre venting and reducing injury tomammalian cells, and increasing the resuscitation rate of injuredmammalian cells, which comprises:

A) a therapeutically effective amount of a therapeutic wound healingcomposition of Embodiment One (I.A-G) selected from the group consistingof:

(I.A.)(a) zinc oxide; and

(b) all forms and precursors of Vitamins A; and

(c) all forms and precursors of Vitamin D.

(I.B) (a) zinc oxide; and

(b) all forms and precursors of Vitamin A; and

(c) all forms and precursors of Vitamin D;

(d) all forms and precursors of Vitamin E.

(I.C) (a) zinc oxide; and

(b) all forms and precursors of Vitamin A; and

(c) all forms and precursors of Vitamin D; and

(d) all forms and precursors of Vitamin K.

(I.D) (a) zinc oxide; and

(b) all forms and precursors of Vitamin A; and

(c) all forms and precursors of Vitamin D; and

(d) all forms and precursors of Vitamin E; and

(e) all forms and precursors of Vitamin K.

(I.E) (a) all forms and precursors of Vitamin A; and

(b) all forms and precursors of Vitamin D; and

(c) all forms and precursors of Vitamin E.

(I.F) (a) all forms and precursors of Vitamin A; and

(b) all forms, and precursors of Vitamin D; and

(c) all forms and precursors of Vitamin E; and

(d) all forms precursors of Vitamin K.

(I.G) (a) all forms and precursors of Vitamin A; and

(b) all forms and precursor of Vitamin D; and

(c) all forms and precursors of Vitamin K; and

(B) a pharmaceutically acceptable carrier.

The pharmaceutically acceptable carrier may be selected for the groupconsisting of pharmaceutical appliance, topical vehicles, and ingestiblevehicles.

In another specific specific embodiment, the invention is directed to amethod of preparing a therapeutic pharmaceutical composition forpreventing and reducing injury to mammalian cells, and increasing theresuscitation of injured mammalian cells, which comprise the steps of:

(A) providing a therapeutically effective amount of a therapeutic woundhealing composition of Embodiment One (I.A-G) selected from the groupconsisting of:

(I.A.) (a) zinc oxide; and

(b) all forms and precursors of Vitamins A; and,

(c) all forms and precursors of Vitamin D.

(I.B) (a) zinc oxide; and

(b) all forms and precursors of Vitamin A; and

(C) all forms and precursors of Vitamin D;

(c) all forms and precursors of Vitamin E.

(I.C) (a) zinc oxide; and

(b) all forms and precursors of Vitamin A; and

(c) all forms and precursors of Vitamin D; and

(d) all forms and precursors of Vitamin K.

(I.D) (a) zinc oxide; and

(b) all forms and precursors of Vitamin A; and

(c) all forms and precursors of Vitamin D; and

(d) all forms and precursors of Vitamin E; and

(e) all forms and precursors of Vitamin K.

(I.E) (a) all forms and precursors of Vitamin A; and

(b) all forms and precursors of Vitamin D; and

(c) all forms and precursors of Vitamin E.

(I.F) (a) all forms and precursors of Vitamin A; and

(b) all forms and precursors of Vitamin D; and

(c) all forms and precursors of Vitamin E; and

(d) all forms and precursors of Vitamin K.

(I.G) (al) all forms and precursors of Vitamin A and

(b) all forms and precursors of Vitamin D; and

(c) all forms and precursors of Vitamin K; and

(B) finding a pharmaceutically acceptable carrier, and

(C) admixing the therapeutic wound healing composition from step (A) andthe pharmaceutically acceptable carrier from step (B) to form atherapeutic pharmaceutical composition.

The invention is further illustrated by examples which are not intendedto limit the effective scope of the claims.

II. Antibacterial-Wound Healing Compositions

A. Embodiment Two (I.A-G+X+Y)

Applicant has discovered therapeutic antibacterial-wound healingcompositions (I.A-G+X+Y) which comprise an antibacterial agent (X), andan antifungal agent, and the wound healing compositions of EmbodimentOne (I.A-G+X+Y) Preferably, the wound healing composition (I.A)comprises (a) zinc oxide and b) two or more fat soluble vitamins.Antibacterial agents can treat bacterial infections in a patient but donot promote the wound healing process. It is the same with antifungalagents. Wound healing compositions can increase the resuscitation rateof injured mammalian cells and the proliferation rate of new mammaliancells to replace dead cells but do not reduce virus titers. Theapplicant has found that the combination of an antibacterial and/orantifungal agent and a wound healing composition results in atherapeutic antibacterial/antifungal-wound healing composition whichreduces the size, duration, and severity of infected wounds.

The combination of the antibacterial agent, and/or the antifungal agent,and the wound healing compositions of the present invention provides apharmaceutical composition useful for treating infected wounds andhaving an enhanced ability to prevent and reduce injury to mammaliancells and further increase the resuscitation rate of injured mammaliancells. The tissue damage associated with many bacterial diseases isbelieved to be caused by the production of cellular produced activeoxygen species. Combination of the antibacterial agent and the woundhealing compositions may suppress such reactive oxygen-linked tissueinjury.

The antibacterial agents which may be employed in theantibacterial-wound healing therapeutic compositions may be selectedfrom a wide variety of water-soluble and water-insoluble drugs and theiracid addition or metallic salts. Both organic and inorganic salts may beused provided the antibacterial agent maintains its medicament value.The antibacterial agents may be selected from a wide range oftherapeutic agents and mixtures of therapeutic agents which may beadministered in sustained release or prolonged action form. Nonlimitingillustrative specific examples of antibacterial agents include bismuthcontaining compounds, sulfonamides; nitrofurans, metronidazole,tinidazole, nimorazole, benzoic acid; aminoglycosides, macrolides,penicillins, polypeptides, tetracyclines, cephalosporins,chloramphenicol, and clindamycin. Preferably, the antibacterial agent isselected from the group consisting of bismuth containing compounds, suchas, without limitation, bismuth aluminate, bismuth subcitrate, bismuthsubgalate, bismuth subsalicylate, and mixtures thereof; thesulfonamides; the nitrofurans, such as nitrofurazone, nitrofurantoin,and furozolidone; and miscellaneous antibacterials such asmetrotidazole, tinidazole, nimorazole, and benzoic acid; andantibiotics, including the aminoglycosides, such as gentamycin,neomycin, kanamycin, and streptomycin; the macrolides, such aserythromycin, clindamycin, and rifamycin; the penicillins, such aspenicillin G, penicillin V, Ampicillin and amoxicillin; thepolypeptides, such as bactracin and polymyxin; the tetracyclines, suchas chlorotetracycline, oxytetracycline, and doxycycline; thecephalospoins, suck as cephalexin and cephalothin; and miscellaneousantibiotics, such as chloramphenicol, and clindamycin. More preferably,the antibacterial agent is selected from the group consisting of bismuthaluminate, nitrofurantoin, furozolidone, metronidazole, tinidazole,nimorazole, benzoic acid, gentamycin, neomycin, kanamycin, streptomycin,erythromycin, clindamycin, rifamycin, penicillin G, penicillin V,Ampicillin amoxicillin, bacitracin, polymyxin, tetracycline,chlorotetracycline, oxytetracycline, doxycycline, cephalexin,cephalothin, chloramphenicol, and clidamycin.

The antibacterial agent of the present invention may be used in manydistinct physical forms well known in the pharmaceutical art to providean initial dosage of the antibacterial agent and/or a furthertime-release form of the antibacterial agent. Without being limitedthereto, such physical forms include free forms and encapsulated forms,and mixtures thereof.

The amount of antibacterial agent which may be employed in theantibacterial-wound healing therapeutic compositions of the presentinvention may vary depending upon the therapeutic dosage recommended orpermitted for the particular antibacterial agent. In general the amountof antibacterial agent present is the ordinary dosage required to obtainthe desired result. Such dosages are known to the skilled practitionerin the medical arts and are not a part of the present invention. In apreferred embodiment, the antibacterial agent in the antibacterial-woundhealing composition is present in an amount from 0.01% to about 10%,preferably from about 0.1% to about 5%, and more preferably from about1% to about 3%, by weight.

In the preferred embodiments of applicant's invention the antifungalagent is selected from the group consisting of astemizole,chlotrimazole, omeprazole, econazole, oxicanazole, salconazole,fluconazole, ketoconazole, itraconazole, terbinafine, and mixturesthereof.

B. Methods for Making the Antibacterial/Antifungal-Wound HealingCompositions of Embodiment Two (I.A-G+X+Y).

The present invention extends to methods for making the therapeuticantibacterial/antifungal-wound healing compositions (I.A-G+X+Y). Ingeneral, a therapeutic antibacterial/antifungal-wound healingcomposition is made by forming an admixture of the wound healingcomponents of Embodiment One (I.A-G) and an antibacterial agent and/oran antifungal agent. In a first aspect of Embodiment Two (I.A-G+X+Y), anantibacterial wound therapeutic composition is made by forming anadmixture of an antibacterial agent, an antifungal agent, and a woundhealing composition comprising (a) zinc oxide. (b) two or more fatsoluble vitamins. In a second aspect of Embodiment Two (I.A-G+X), anantibacterial-wound healing therapeutic composition is made by formingan admixture of an antibacterial agent and a wound healing compositioncomprising (a) zinc oxide, (b) two or more fat soluble vitamins. In athird aspect of Embodiment Two (I.A-G+Y), an antifungal-wound healingtherapeutic composition is made by forming an admixture of anantibacterial agent and a wound healing composition comprising (a) zincoxide, and(b) two or more fat soluble vitamins.

In a preferred embodiment, the invention is directed to a method forpreparing a therapeutic antibacterial-wound healing composition(I.A-G+X) which comprises the steps of admixing the followingingredients:

(A) A therapeutically effective amount of an antibacterial agent; and

(B) a wound healing composition which comprises;

(a) zinc oxide and;

(b) two or more fat soluble vitamins.

C. Methods for Employing the Antibacterial/Antifungal-Wound HealingComposition Embodiment Two (I.A-G+X+Y).

The present invention extends to methods for employing the therapeuticantibacterial-wound healing compositions (I.A-G+X). In general, atherapeutic composition is employed by contacting the therapeuticcomposition with a wound. In a preferred embodiment, the invention isdirected to a method for healing an infected wound in a mammal with anantibacterial-wound healing composition (I.A+X) which comprises thesteps of:

(A) providing a therapeutic antibacterial-wound healing compositionwhich comprises;

-   -   (1) at therapeutically effective amount of an antibacterial        agent; and    -   (2) a wound healing composition which comprises;        -   (a) zinc oxide;        -   (b) two or more fat soluble vitamins; and

(B) contacting the antibacterial-wound healing composition with theinfected or non-infected wound.

D. Methods for Employing the Antibacterial/Antifungal-Wound HealingComposition Embodiment Two (I.A-G+Y).

The present invention extends to methods for employing the therapeuticantifungal-wound healing compositions (I.A-G+Y). In general, atherapeutic composition is employed by contacting the therapeuticcomposition with a wound. In a preferred embodiment, the invention isdirected to a method for healing an infected wound in a mammal with anantifungal-wound healing composition (I.A-G+Y) which comprises the stepsof:

(A) providing a therapeutic antifungal-wound healing composition whichcomprises;

-   -   (1) a therapeutically effective amount of an antifungal agent;        and    -   (2) a wound heating composition which comprises;        -   (a) zinc oxide;        -   (b) two or more fat soluble vitamins; and

(B) contacting the antifungal-wound healing composition with theinfected or non-infected wound.

E. Augmented Antibacterial/Antifungal-Wound Healing Compositions ofEmbodiment Two (I.A-G+X+Y+M)

In another aspect of Embodiment Two, the therapeuticantibacterial/antifungal-wound healing compositions (I.A-G+X+Y) of thepresent invention man be further combined with medicaments useful fortreating wounds (M) to form augmented antibacterial/antifungal-woundhealing compositions (I.A-G+X+Y+M). In this embodiment, the combinationof the antibacterial/antifungal-wound healing composition of the presentinvention and the medicament useful for treating wounds provides anaugmented antibacterial-wound healing composition having an enhancedability to increase the proliferation and resuscitation rate ofmammalian cells. For example, the therapeutic compositions of thepresent invention may be used in combination with medicaments useful fortreating wounds such as immunostimulating agents (BETAFECTIN®),antiviral agents, antikeratolytic agents, anti-inflammatory agents,antifungal agents, tretinoin, sunscreen agents, dermatological agents,topical antihistamine agents, other antibacterial agents, bioadhesiveagents, respiratory bursting inhibitors (lactic acid, adenosine),inhibitors of prostaglandin synthesis (ibuprofen, aspirin, indomethacin,meclofenomic acid, retinoic acid, padimate O, melcomen, oxybenzone),steroidal anti-flammatory agents (corticosteroids including syntheticanalogs), antimicrobial agents (NEOSPORIN® ointment, silvadine),antiseptic agents anesthetic agents (pramoxine hydorchloride, lidocaine,benzocaine) cell nutrient media burn relief medication, sun burnmedications, acne preparations, insect bite and sting medications, woundcleansers, wound dressings, scar reducing agents (Vitamin E), and thelike, and mixtures thereof, to further enhance the proliferation andresuscitation rate of mammalian cells. Preferably, the medicament usefulfor treating wounds is selected from the group consisting ofimmunostimulating agents, antiviral agents, antikerotolytic agents,anti-inflammatory agents, antifungal agents, tretinoin, sunscreenagents, dermatological agents, topical antihistamine agents,antibacterial agents, bioadhesive agents, respirators burstinginhibitors, inhibitors of prostaglandin synthesis, antimicrobial agents,cell nutrient media, scar reducing agents, and mixtures thereof. Morepreferably, the medicament useful for treating wounds is selected fromthe group consisting of immunostimulating agents, antiviral agents,antikeratolytic agents, anti-inflammatory agents, antifungal agents,acne treating agents, sunscreen agents, dermatological agents,antihistamine agents, antibacterial agents, bioadhesive agents, andmixtures thereof.

In a preferred embodiment, the invention is directed to an augmentedantibacterial/antifungal-wound healing composition (I.A+X+Y+M) whichcomprises:

(A) a therapeutic antibacterial/antifungal-wound healing compositionwhich comprises:

-   -   (1) a therapeutically effective amount of an antibacterial        agent; and/or    -   (2) a therapeutically effective amount of an antifungal agent;        and    -   (3) a wound healing composition which comprises:        -   (a) zinc oxide; and        -   (b) two or more fat soluble vitamins; and

(B) a medicament useful for treating wounds.

The present invention extends to methods for making the augmentedantibacterial/antifungal-wound healing compositions. In general, theaugmented compositions are made by admixing the therapeuticantibacterial/antifungal-wound healing composition with the medicamentuseful for treating wounds to prepare the augmentedantibacterial/antifungal-wound heating composition.

The present invention also extends to methods for employing theaugmented antibacterial/antifungal-wound healing compositions. Ingeneral, an augmented antibacterial/antifungal-wound healing compositionis employed by contacting the composition with a wound. In a preferredembodiment, the invention is directed to a method for healing aninfected or non-infected wound in a mammal with an augmentedantibacterial/antifungal-wound healing composition (I.A+X+Y+M) whichcomprises the steps of

(A) providing a therapeutic augmented antibacterial/antifungal-woundhealing composition which comprises:

-   -   (1) a therapeutically effective amount of an antibacterial        agent; and/or    -   (2) a therapeutically effective amount of antifungal agent;    -   (3) a wound healing composition which comprises:        -   (a) zinc oxide; and        -   (b) two or more fat soluble vitamins; and    -   (4) contacting the medicament useful for treating wounds; and

(B) contacting the augmented antibacterial-wound healing compositionwith the infected wound.

The types of wounds which may be healed using theantibacterial/antifungal-wound healing compositions and the augmentedantibacterial/antifungal-wound healing compositions of the presentinvention are those which result from an infected injury which causesepidermal and tissue damage. The topical therapeutic compositions may beused orally in the form of a mouth wash or spray to protect andaccelerate the healing of injured oral tissue.

Methods for healing a wound comprise topically administering thecompositions of the present invention directly to a wound site toincrease the healing rate of the wound the composition is maintained incontact with the wound for a period of time sufficient to increase theproliferation and resuscitation rate of the cells.

E. Formulations of the Antibacterial/Antifungal-Wound HealingCompositions of Embodiment Two (I.A-G+X+Y) and (I.A-G+X+M).

Once prepared, the inventive therapeutic antibacterial-wound healingcompositions and augmented antibacterial/antifungal-wound healingcompositions may be stored for future use or may be formulated ineffective amounts with pharmaceutically acceptable carriers such apharmaceutical appliances and topical vehicles (oral and non-oral) toprepare a wide variety of pharmaceutical compositions. Thepharmaceutically acceptable carriers which may be employed and themethods used to prepare the pharmaceutical compositions have beendescribed above in connection with the formulations of the wound healingcompositions of Embodiment One (I.A-G).

In a preferred embodiment the invention is directed to anantibacterial/antifungal-wound healing pharmaceutical-wound healingpharmaceutical composition which comprises:

(A) a therapeutic antibacterial-wound healing composition (I.A-G+X+Y)which comprises:

-   -   (1) a therapeutically effective amount of an antibacterial        agent; and    -   (2) a therapeutically effective amount of an antifungal agent;        and    -   3) a wound healing composition which comprises:        -   (a)zinc oxide; and        -   (b) two or more fat soluble vitamins; and

(B) a pharmaceutically acceptable carrier selected from the groupconsisting of pharmaceutical appliances, bioadhesives, and occlusivevehicles.

In another preferred embodiment, the invention is directed to a methodfor preparing a pharmaceutical composition for increasing theproliferation and resuscitation rate of mammalian cells, which comprisesthe steps of.

(A) providing a therapeutically effective amount of anantibacterial/antifungal-wound healing composition (I.A-G+X+Y) whichcomprises:

-   -   (1) an antibacterial agent; and    -   (2) an antifungal agent; and    -   (3) a wound healing composition comprising        -   (a) zinc oxide        -   (b) two or more fat soluble vitamins; and

(B) providing a pharmaceutically carrier; and

(C) Admixing the antibacterial/antifungal-wound healing composition fromstep (A) and the pharmaceutically acceptable carrier from step (B) toform a pharmaceutical composition.

I claim:
 1. A therapeutic tissue healing composition adapted for oraland non-oral application in mammals comprising: an effective amount of amixture of zinc oxide, fat-soluble vitamins A, D, E, K, an effectiveamount of an antibacterial agent, an effective amount of an antifungalagent, and an effective amount of calcium channel blocker.
 2. Thecomposition of claim 1, wherein said calcium channel blocker is3,5-pyridinedicarboxylic acid,1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-dimethyl ester, which has thechemical formula of C₁₇H₁₈N₂O₆.
 3. The composition of claim 1, whereinsaid Vitamin A is selected from the group consisting of retinol,3,4-didehydroretinol, carotene, alpha-carotene, beta-carotene,delta-carotene, and gamma carotene.
 4. The composition of claim 1,wherein said Vitamin D is selected from the group consisting ofcholecalciferol and ergocalciferol.
 5. The composition of claim 1,wherein said Vitamin E is selected from the group consisting of VitaminE acetate, Vitamin E succinate, pharmaceutically acceptable Vitamin Esalts and Vitamin E phosphate.
 6. The composition of claim 1, whereinsaid antibacterial agent is selected from the group consisting ofbismuth-containing compounds, sulfonamides, nitrofurans, metronidazole,nimorazole, tinidazole, benzoic acid, aminoglycosides, macrolides,penicillins, polypeptides, tetracyclines, cephalosporins,chloramphenicol, clindamycin and mixtures thereof.
 7. The composition ofclaim 1, wherein said antibacterial agent is selected from the groupconsisting of bismuth aluminate, bismuth subcitrate, bismuth subgalate,bismuth subsalicylate, sulfonamides, nitrofurazone, nitrofurantoin,furazolidone, metronidazole, tinidazole, nimorazole, benzoic acid,neomycin, kynamycin, streptomycin, erythromycin, clindamycin, rifampin,rifamycin, penicillin G, penicillin V, ampicillin, amoxicillin,bacitracin, polymixin, tetracycline, chlorotetracycline,oxytetracycline, doxycycline, cephalexin, cephalothin, chloramphenicoland mixtures thereof.
 8. The composition of claim 1, wherein saidantibacterial agent is bacitracin zinc.
 9. The composition of claim 1,wherein said antifungal agent is selected from the group consisting ofastemizole, clotrimazole, omeprazole, econazole, oxiconazole,sulconazole, fluconazole, ketoconazole, itraconazole, terbinafine, andmixtures thereof.
 10. The composition of claim 1, wherein saidantifungal agent is clotrimazole.
 11. The composition of claim 1,wherein said Vitamin A is retinyl palmitate, said Vitamin D isergocalciferol, and said Vitamin E is tocopherol.
 12. A wound healingcomposition for repairing human skin tissue adapted for oral andnon-oral administration, comprising: a therapeutically effective mixtureof zinc oxide, a calcium channel blocker, at least two fat-solublevitamins admixed with a pharmaceutically acceptable carrier, anantibacterial agent and an antifungal agent, admixed in therapeuticallyeffective amounts.
 13. The composition of claim 12, wherein saidfat-soluble vitamins comprise at least Vitamins A and D.
 14. Thecomposition of claim 13, further comprising therapeutically effectiveamounts of Vitamins E and K.
 15. The composition of claim 14, whereinsaid calcium channel blocker is nifedipine.
 16. The composition of claim15, wherein the therapeutically effective mixture contains between about0.01% and about 75% by total weight of zinc oxide, between about 0.01%and 99.99% by total weight of combined amount of fat-soluble vitamins,and between 0.0001% and 50% by total weight of nifedipine.
 17. A methodof healing wounds in mammals by repairing body tissue in mammals,comprising the steps of: contacting a wound to be healed with atherapeutic composition comprising an effective amount of thecomposition of claim
 1. 18. A method of healing wounds in mammals byrepairing body tissue in mammals, comprising the steps of: contacting awound to be healed with a therapeutic composition comprising aneffective amount of the composition of claim
 2. 19. A method of healingwounds in mammals by repairing body tissue in mammals, comprising thesteps of: contacting a wound to be healed with a therapeutic compositioncomprising an effective amount of the composition of claim
 3. 20. Amethod of healing wounds in mammals by repairing body tissue in mammals,comprising the steps of: contacting a wound to be healed with atherapeutic composition comprising an effective amount of thecomposition of claim
 4. 21. A method of healing wounds in mammals byrepairing body tissue in mammals, comprising the steps of: contacting awound to be healed with a therapeutic composition comprising aneffective amount of the composition of claim
 5. 22. A method of healingwounds in mammals by repairing body tissue in mammals, comprising thesteps of: contacting a wound to be healed with a therapeutic compositioncomprising an effective amount of the composition of claim
 6. 23. Amethod of healing wounds in mammals by repairing body tissue in mammals,comprising the steps of: contacting a wound to be healed with atherapeutic composition comprising an effective amount of thecomposition of claim
 7. 24. A method of healing wounds in mammals byrepairing body tissue in mammals, comprising the steps of: contacting awound to be healed with a therapeutic composition comprising aneffective amount of the composition of claim
 8. 25. A method of healingwounds in mammals by repairing body tissue in mammals, comprising thesteps of: contacting a wound to be healed with a therapeutic compositioncomprising an effective amount of the composition of claim
 9. 26. Amethod of healing wounds in mammals by repairing body tissue in mammals,comprising the steps of: contacting a wound to be healed with atherapeutic composition comprising an effective amount of thecomposition of claim
 10. 27. A method of healing wounds in mammals byrepairing body tissue in mammals, comprising the steps of: contacting awound to be healed with a therapeutic composition comprising aneffective amount of the composition of claim
 11. 28. A method of healingwounds in mammals by repairing body tissue in mammals, comprising thesteps of: contacting a wound to be healed with a therapeutic compositioncomprising an effective amount of the composition of claim
 12. 29. Amethod of healing wounds in mammals by repairing body tissue in mammals,comprising the steps of: contacting a wound to be healed with atherapeutic composition comprising an effective amount of thecomposition of claim
 13. 30. A method of healing wounds in mammals byrepairing body tissue in mammals, comprising the steps of: contacting awound to be healed with a therapeutic composition comprising aneffective amount of the composition of claim
 14. 31. A method of healingwounds in mammals by repairing body tissue in mammals, comprising thesteps of: contacting a wound to be healed with a therapeutic compositioncomprising an effective amount of the composition of claim
 15. 32. Amethod of healing wounds in mammals by repairing body tissue in mammals,comprising the steps of: contacting a wound to be healed with atherapeutic composition comprising an effective amount of thecomposition of claim 16.